Heteroarylcarbamoylbenzene derivative

ABSTRACT

Compounds represented by formula (I):  
                 
as well as their pharmaceutically acceptable salts are disclosed. The compounds are useful as glucokinase activating agents for the treatment of diabetes and related conditions. Compositions and methods of treatment are also included.

TECHNICAL FIELD

The present invention relates to glucokinase activators comprisingheteroarylcarbamoylbenzene derivatives as active ingredients. Theinvention further relates to novel heteroarylcarbamoylbenzenederivatives.

SUMMARY OF THE INVENTION

Glucokinase (GK) (ATP:D-hexose 6-phosphotransferase, EC2.7.1.1) is oneof the four types of mammalian hexokinases (hexokinase IV). Hexokinasesare enzymes in the first step of the glycolysis pathway which catalyzethe reaction from glucose to glucose-6-phosphate. Expression ofglucokinase is largely localized in the liver and pancreatic beta cells,and it plays an important role in glucose metabolism throughout the bodyby controlling the rate limiting step of glucose metabolism in thesecells. The glucokinase types expressed in the liver and pancreatic betacells differ in the sequence of the 15 N-terminal amino acids due to adifference in splicing, but their enzymatic properties are identical.The enzyme activities of the three hexokinases (I, II, III) other thanglucokinase become saturated at a glucose concentration of below 1 mM,whereas the Km of glucokinase for glucose is 8 mM, or close to thephysiological glucose level. Thus, glucokinase-mediated intracellularglucose metabolism is accelerated in response to glucose level changesby postprandial glucose level increase (10-15 mM) from normal glucose (5mM).

The theory that glucokinase acts as a glucose sensor for pancreatic betacells and the liver has been advocated for about 10 years (for example,Garfinkel D. et al., Computer modeling identifies glucokinase as glucosesensor of pancreatic beta cells, American Journal Physiology, Vol. 247(3Pt2)1984, p 527-536).

Recent results in glucokinase gene-manipulated mice have confirmed thatglucokinase does in fact play an important role in systemic glucosehomeostasis. Mice lacking a functional glucokinase gene die shortlyafter birth (for example, Grupe A. et al., Transgenic knockouts reveal acritical requirement for pancreatic beta cell glucokinase in maintainingglucose homeostasis, Cell, Vol. 83, 1995, p 69-78), while healthy anddiabetic mice overexpressing glucokinase have lower blood glucose levels(for example, Ferre T. et al., Correction of diabetic alterations byglucokinase, Proceedings of the National Academy of Sciences of theU.S.A., Vol. 93, 1996, p 7225-7230). With glucose level increase, thereactions of pancreatic beta cells and the liver, while differing, bothact toward lowering blood glucose. Pancreatic beta cells secrete moreinsulin, while the liver takes up glucose and stores it as glycogenwhile also reducing glucose release.

Such variation in glucokinase enzyme activity is important for liver andpancreatic beta cell-mediated glucose homeostasis in mammals. A mutantform of the glucokinase gene is expressed in a type of diabetes whichoccurs in youth, known as MODY2 (maturity-onset diabetes of the young),and the reduced glucokinase activity has been shown to be responsiblefor blood glucose increase (for example, Vionnet N. et al., Nonsensemutation in the glucokinase gene causes early-onsetnon-insulin-dependent diabetes mellitus, Nature Genetics, Vol. 356,1992, p 721-722).

On the other hand, families have been found having a mutation whichincreases glucokinase activity, and such individuals exhibithypoglycemic symptoms (for example, Glaser B. et al., Familialhyperinsulinism caused by an activating glucokinase mutation, NewEngland Journal Medicine, Vol. 338, 1998, p 226-230).

This suggests that in humans as well, glucokinase functions as a glucosesensor and thus plays an important role in glucose homeostasis. Glucoseregulation utilizing a glucokinase sensor system should be possible toachieve in type II diabetic patients. Since glucokinase activatorsshould have effects of accelerating insulin secretion by pancreatic betacells and of promoting glucose uptake and inhibiting glucose release bythe liver, they are potentially useful as therapeutic agents for type IIdiabetic patients.

In recent years it has been demonstrated that pancreatic beta cellglucokinase is expressed locally in rat brain, and particularly in theventromedial hypothalamus (VMH). Approximately 20% of VMH neurons areknown as “glucose-responsive neurons”, and these have long beenconsidered to play an important role in body weight control.Administration of glucose into rat brain reduces feeding consumption,but inhibiting glucose metabolism by intracerebral administration of theglucose analog glucosamine produces hyperphagia. Electrophysiologicalexperiments have indicated that glucose-responsive neurons are activatedin response to physiological glucose level changes (5-20 mM) but thattheir activation is inhibited with glucose metabolism inhibition byglucosamine or the like. The glucose level-detecting system in the VMHis believed to be based on a glucokinase-mediated mechanism similar tothat for insulin secretion by pancreatic beta cells. Consequently,substances which activate glucokinase in the VMH in addition topancreatic beta cells not only exhibit a glucose rectifying effect butcan also potentially rectify obesity, which is a problem for most typeII diabetic patients.

This indicates that compounds having glucokinase-activating effects areuseful as therapeutic and/or prophylactic agents for diabetes, astherapeutic and/or prophylactic agents for diabetes complications suchas retinopathy, nephropathy, neuropathy, ischemic cardiopathy,arteriosclerosis and the like, and as therapeutic and/or prophylacticagents for obesity.

The compound represented by the following formula (IV), havingsubstituents at the 3- and 5-positions of the same benzene ring as theheteroarylcarbamoylbenzene derivatives (I) of the invention, has beendescribed.

This compound has tert-butyl groups at both the 3- and 5-positions ofthe heteroarylcarbamoylbenzene ring, and does not have alkyl groups atthe 3- and 5-positions as according to the compounds of the invention.It also has imidazo-[1,2-a]pyridine bonded to the nitrogen atom of thecarbamoyl group, but the relative positional relationship between the Nof the pyridine ring of the imidazo-[1,2-a]pyridyl group and thecarbamoyl group differs from the relative positional relationshipbetween the carbamoyl group and the nitrogen atom of the heteroarylgroup in the compounds of the invention (for example, Japanese Laid-OpenPublication of International Application No. 11-505524).

The compound represented by the following formula (V), having twosubstituents on the benzene ring of a heteroarylcarbamoylbenzenederivative, has also been described (for example, Japanese Laid-OpenPublication of International Application No. 2001-526255).

Although the compound described in the aforementioned Patent document 2partially matches the structure of the compounds of the invention inthat one of the two substituents is trifluoromethylphenylamino,trifluoromethylphenylamino being included in the X¹-(Ring A)-R¹ of thecompounds of the invention, and in that it contains a pyridine ring asthe group bonded to the nitrogen atom of the carbamoyl group, in thecompounds of the invention the nitrogen atom of the pyridine ring bondedto the nitrogen atom of the carbamoyl group is adjacent to the carbonatom of the pyridine ring which is bonded to the nitrogen atom of thecarbamoyl group, whereas the compound described in the aforementionedPatent document 2 differs in that the nitrogen atom is bonded viaanother carbon atom lying between it and the carbon atom of the pyridinering which is bonded to the nitrogen atom of the carbamoyl group, andalso in that the bonding position of the methoxy group is different fromthe bonding position of the compounds of the invention.

The compound represented by the following formula (VI) has also beendescribed (for example, Japanese Laid-Open Publication of InternationalApplication No. 2002-509536).

Although the compound described in the aforementioned Patent document 3matches the structure of the compounds of the invention in that one ofthe two substituents on the benzene ring is 2-methyl-4-iodo-phenylaminoand in that a nitrogen atom is adjacent to the carbon atom bonded to thenitrogen atom of the carbamoyl group, it differs in that the positionalrelationship between the 2-methyl-4-iodo-phenylamino group and thecarbamoyl group is different from the positional relationship in thecompounds of the invention, and in that it has a fluoro group as theother of the two substituents on the benzene ring while the compounds ofthe invention contain no halogen atoms as substituents on the benzenering.

DISCLOSURE OF THE INVENTION

As a result of diligent research directed toward developing noveldiabetes drugs having novel drug effects which also exceed the drugeffects of existing diabetes drugs, due to action differing from that ofthe existing drugs, the present inventors have found that compoundsrepresented by formula (I) shown below have glucokinase-activatingeffects, and the invention has been completed on the basis of thisfinding. Specifically, the present invention relates to the following.

(1) Compounds represented by the following formula (I):

[wherein X¹ represents oxygen, sulfur or NH, X² represents oxygen,sulfur or CH₂, R¹ represents 1 or 2 substituents optionally present onRing A which are selected from the group consisting of alkylsulfonyl,alkanoyl, lower alkyl, hydroxyalkyl, hydroxy, alkylcarbamoyl,alkylsulfamoyl, dialkylsulfamoyl, alkylthio, alkoxy, dialkylcarbamoyl,alkoxycarbonylamino, alkoxycarbonyl, halogen atoms, alkanoylaminoalkyl,alkoxycarbonylaminoalkyl, alkylsulfonylaminoalkyl, cyano andtrifluoromethyl, R² represents a C3-7 cyclic alkyl group (wherein one ofthe constituent carbon atoms of the ring (except for the carbon atom,among the constituent carbon atoms of the ring, which is bonded to X²)is optionally replaced with oxygen, NH, N-alkanoyl or CONH), astraight-chain or branched lower alkyl group or a lower alkenyl group,optionally having a substituent selected from the group consisting ofhalogen atoms, carboxyl, alkoxycarbonyl, hydroxy, amino (where the aminomay be further substituted with 1 or 2 alkanoyl or lower alkyl groups),alkoxy and N-alkylcarbamoyl, R³ represents 1 or 2 substituentsoptionally present on Ring B which are selected from the groupconsisting of lower alkyl, alkoxy, alkylamino, lower dialkylamino,halogen atoms, trifluoromethyl, hydroxyalkyl (wherein the hydrogen ofthe hydroxy in the hydroxyalkyl group may be replaced with lower alkyl),aminoalkyl, alkanoyl, carboxyl, alkoxycarbonyl and cyano, the followingformula (II):

represents a 6- to 10-membered aryl group or 5- to 7-membered heteroarylgroup optionally having on the ring 1 or 2 substituents represented byR¹ above, and the following formula (III):

represents a monocyclic or bicyclic heteroaryl group optionally havingon the ring 1 or 2 substituents represented by R³ above, wherein thecarbon atom of Ring B which is bonded to the nitrogen atom of the amidegroup of formula (I) forms a C═N bond with the nitrogen atom of thering], and their pharmaceutically acceptable salts;

(2) Compounds according to (1) above, wherein X¹ is O or S, and X² is Oor CH₂;

(3) Compounds according to (2) above, wherein Ring A is a phenyl groupor a 5- to 6-membered heteroaryl group;

(4) Compounds according to (2) above wherein Ring A is a phenyl group;

(5) Compounds according to (2) above wherein Ring A is a 5- to6-membered heteroaryl group;

(6) Compounds according to any one of (4) to (5) above, wherein R¹ ishydrogen, alkylsulfonyl, alkanoyl, hydroxyalkyl, alkylcarbamoyl,alkylsulfamoyl, dialkylsulfamoyl, dialkylcarbamoyl, alkoxycarbonylamino,halogen atoms, alkanoylaminoalkyl, alkylsulfonylaminoalkyl oralkoxycarbonylaminoalkyl;

(7) Compounds according to (4) above, wherein R¹ is alkylsulfonyl,alkanoyl, hydroxyalkyl, alkanoylaminoalkyl, alkylsulfonylaminoalkyl oralkoxycarbonylaminoalkyl;

(8) Compounds according to (4) above, wherein R¹ is alkylsulfonyl,alkanoyl or hydroxyalkyl;

(9) Compounds according to any one of (3) to (8) above, wherein formula(M) represents a monocyclic or bicyclic heteroaryl group (provided thatthe heteroaryl group is not 5-alkoxycarbonyl-pyridin-2-yl or5-carboxyl-pyridin-2-yl) optionally having on the ring 1 or 2substituents represented by R³ above, wherein the carbon atom of Ring Bwhich is bonded to the nitrogen atom of the amide group of formula (1)forms a C═N bond with the nitrogen atom of Ring B;

(10) Compounds according to (7) above, wherein Ring B has at least onehetero atom in the ring selected from the group consisting of nitrogen,sulfur and oxygen atoms, in addition to the nitrogen atom forming theC═N group together with the carbon atom in the ring which is bonded tothe nitrogen atom of the amide group in formula (I);

(11) Compounds according to any one of (1) to (10) above, wherein R² isa C3-7 cyclic alkyl group (wherein one of the constituent carbon atomsof the ring is optionally replaced with oxygen, NH or N-alkanoyl), astraight-chain or branched lower alkyl group or a lower alkenyl group,optionally substituted with a halogen atom, carboxyl, alkoxycarbonyl,hydroxy, amino (where the amino may be further substituted with 1 or 2lower alkyl groups), alkoxy, N-alkylcarbamoyl or alkanoylamino;

(12) Compounds according to any one of (1) to (11) above, wherein Ring Bis thiazolyl, imidazolyl, isothiazolyl, thiadiazolyl, triazolyl,oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrimidinyl,pyridothiazolyl or benzothiazolyl;

(13) Compounds according to any one of (1) to (12) above, wherein R³ islower alkyl, alkoxy, a halogen, hydroxyalkyl (wherein the hydrogen ofthe hydroxy in the hydroxyalkyl group may be replaced with lower alkyl),aminoalkyl or alkanoyl;

(14) Compounds according to any one of (1) to (12) above, wherein R³ islower alkyl or hydroxyalkyl (wherein the hydrogen of the hydroxy in thehydroxyalkyl group may be replaced with lower alkyl);

(15) Compounds represented by formula (I):

[wherein the symbols have the same definitions specified above], whichare5-isopropoxy-3-(4-methanesulfonylphenoxy)-N-(4-methylthiazol-2-yl)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,5-ethoxy-3-(4-methanesulfonylphenoxy)-N-(4-methoxymethyl-thiazol-2-yl)benzamide,5-cyclopentyloxy-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,3-(4-methanesulfonylphenoxy)-5-(tetrahydrofuran-3-yloxy)-N-thiazol-2-yl-benzamide,3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide,3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methoxymethyl-ethoxy)-N-thiazol-2-yl-benzamide,3-(2-fluoro-4-methanesulfonylphenoxy)-5-isopropoxy-N-thiazol-2-yl-benzamide,3-(4-methanesulfonylphenoxy)-5-(1-methoxymethyl-propoxy)-N-(4-methyl-thiazol-2-yl)-benzamide,5-isopropoxy-3-(4-methanesulfonylphenoxy)-N-pyrazol-3-yl-benzamide,5-isopropoxy-3-(4-methanesulfonylphenoxy)-N-pyrazin-2-yl-benzamide,3-(4-methanesulfonylphenoxy)-5-(3-methoxy-1-methyl-propoxy)-N-thiazol-2-yl-benzamide,5-(3-hydroxy-1-methyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(4-methanesulfonylphenoxy)-N-pyrimidin-4-yl-benzamide,5-isopropoxy-3-(4-methanesulfonylphenoxy)-N-(pyrimidin-2-yl)-benzamide,N-(4-hydroxymethyl-thiazol-2-yl)-5-isopropoxy-3-(4-methanesulfonylphenoxy)-benzamide,N-(isooxazol-3-yl)-3-(4-methanesulfonylphenoxy)-5-(1-methoxymethyl-propoxy)-benzamide,3-(4-methanesulfonylphenoxy)-5-(1-methoxymethyl-propoxy)-N-[1,3,4]thiadiazol-2-yl-benzamide,5-(1-hydroxymethyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-(4-methyl-thiazol-2-yl)-benzamide,N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methanesulfonylphenoxy)-5-(1-methoxymethyl-propoxy)-benzamide,5-(2-amino-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,5-(2-dimethylamino-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-propoxy)-3-(4-methanesulfonylphenoxy)-N-(4-methyl-thiazol-2-yl)-benzamide,3-(4-methanesulfonylphenoxy)-5-(2-methoxy-propoxy)-N-(4-methyl-thiazol-2-yl)-benzamide,5-isopropoxy-3-(4-methanesulfonylphenoxy)-N-(thiazolo[5,4-b]pyridin-2-yl)-benzamide,5-(2-hydroxymethyl-allyl)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazolo[5,4-b]pyridin-2-yl-benzamide,5-(3-hydroxy-2-methyl-propyl)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,3-(4-methanesulfonylphenoxy)-N-(4-methyl-thiazol-2-yl)-5-(piperidin-4-yl-oxy)-benzamidehydrochloride,5-(1-acetyl-piperidin-4-yloxy)-3-(4-methanesulfonylphenoxy)-N-(4-methyl-thiazol-2-yl)-benzamide,2-[3-(4-methanesulfonylphenoxy)-5-(4-methyl-thiazol-2-yl-carbamoyl)-phenoxy]propionicacid,5-(3-hydroxy-1-methyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,3-(4-methanesulfonylphenoxy)-5-(1-methylcarbamoyl-ethoxy)-N-(4-methyl-thiazol-2-yl)-benzamide,5-(2-acetylamino-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-5-isopropoxy-3-(4-methanesulfonylphenoxy)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-pyridin-2-yl-benzamide,5-(2-hydroxy-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-cyclopentyloxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,N-(4-acetyl-thiazol-2-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methanesulfonylphenoxy)-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-benzamide,3-(3-fluoro-4-methanesulfonylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(5-methyl-thiazol-2-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-([1,2,4]thiadiazol-5-yl)-benzamide,N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(5-methoxycarbonyl-pyridin-2-yl)-benzamide,6-[5-isopropoxy-3-(4-methanesulfonylphenoxy)-benzoylamino]nicotinicacid,5-(2-hydroxy-1-methyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)-3-(4-methanesulfonylphenoxy)-benzamide,N-(5-hydroxymethyl-thiazol-2-yl)-5-isopropoxy-3-(4-methanesulfonylphenoxy)-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-benzamide,N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methanesulfonylphenoxy)-5-(tetrahydrofuran-3-yl-oxy)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(2-methylthiazol-4-yl)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(4-methoxymethyl-thiazol-2-yl)-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-3-(4-methanesulfonylphenoxy)-5-(tetrahydrofuran-3-yl-oxy)-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-3-(4-methanesulfonylphenoxy)-5-(tetrahydrofuran-3-yl-oxy)-benzamide,N-(2,5-dimethylthiazol-4-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-benzamide,5-isopropoxy-3-(4-methoxycarbonylaminomethylphenoxy)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(4-methylcarbamoyl-phenoxy)-N-thiazol-2-yl-benzamide,3-(4-dimethylcarbamoyl-phenoxy)-5-isopropoxy-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(4-methylcarbonylaminomethyl-phenoxy)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(4-methanesulfonylaminomethyl-phenoxy)-N-thiazol-2-yl-benzamide,3-[4-(1-hydroxy-propyl)-phenoxy]-5-isopropoxy-N-thiazol-2-yl-benzamide,6-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl)-phenoxy]-nicotinic acid methylester,3-(5-hydroxymethyl-pyridin-2-yl-oxy)-5-isopropoxy-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(5-methanesulfonylpyridin-2-yl)-N-thiazol-2-yl-benzamide,3-(5-acetyl-pyridin-2-yl-oxy)-5-isopropoxy-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(5-methoxycarbonyl-pyrazin-2-yl-oxy)-N-thiazol-2-yl-benzamide,3-(5-cyano-pyridin-2-yl-oxy)-5-isopropoxy-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridin-4-yl-oxy)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridin-3-yl-oxy)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridin-3-yl-oxy)-N-thiazolo[5,4-b]pyridin-2-yl-benzamide,5-isopropoxy-3-([1,3,4]thiadiazol-2-ylsulfanyl)-N-thiazolo[5,4-b]-pyridine-2-yl-benzamide,5-isopropoxy-3-(4-methyl-[1,2,4]triazol-3-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-thiazol-2-ylsulfanyl-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(4H-[1,2,4]triazol-3-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-([1,3,4]thiadiazol-2-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(5-methylsulfanyl-[1,3,4]thiadiazol-2-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-(tetrahydrofuran-3-yl-oxy)-N-thiazol-2-yl-3-(4H-[1,2,4]triazol-3-ylsulfanyl)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(4-methyl-thiazol-2-yl)-3-([1,3,4]thiadiazol-2-ylsulfanyl)-benzamide,5-(3-hydroxy-1-methyl-propoxy)-N-(4-methyl-thiazol-2-yl)-3-([1,3,4]thiadiazol-2-ylsulfanyl)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-([1,3,4]thiadiazol-2-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenylsulfanyl)-N-thiazol-2-yl-benzamide,3-(3-fluoro-phenylthio)-5-(2-hydroxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(pyridin-4-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methyl-pyridin-3-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(3-methyl-[1,2,4]-thiadiazol-5-yl)-benzamide,N-[3-hydroxymethyl-1,2,4-thiadiazol-5-yl]-3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)benzamide,5-(3-hydroxy-1-methylethoxy)-3-(4-methanesulfonylphenoxy)-N-[5-methyl-1,2,4-thiadiazol-3-yl]benzamide,5-(hydroxy-1-methylethoxy)-3-(4-methanesulfonylphenoxy)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(1,2,5-thiadiazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(4-trifluoromethyl-thiazol-2-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(4,5,6,7-tetrahydrobenzothiazol-2-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(pyridazin-3-yl)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(3-isopropyl-[1,2,4]-triazol-5-yl)-3-(4-methanesulfonylphenoxy)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(3-methyl-[1,2,4]-oxadiazol-5-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-thiazol-2-yl]-3-(4-methanesulfonylphenoxy)benzamide,N-(4-cyano-thiazol-2-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(1-hydroxymethyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-(pyridin-2-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(5-methyl-isothiazol-3-yl)benzamide,5-(3-hydroxy-cyclopentyloxy)-3-(4-methanesulfonylphenoxy)-N-(thiazol-2-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(5-methoxy-thiazol-2-yl)benzamide,5-(1-hydroxymethyl-2-methyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-(thiazol-2-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(1H-[1,2,3]triazol-4-yl)benzamide,N-(1-acetyl-1H-pyrazol-3-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(pyrazol-3-yl)benzamide,N-(5,6-dihydro-4H-cyclopentathiazol-2-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)benzamide,5-(1-hydroxymethyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(thieno[3,2-d]thiazol-2-yl)benzamide,3-(3-fluoro-4-methanesulfonylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-N-(pyrazol-3-yl)benzamide,3-(4-cyano-phenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(4-ethylsulfonylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(3-hydroxy-1-methyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(4-ethanesulfonylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-isopropylsulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(4-hydroxy-4-methyl-4,5,6,6a-tetrahydro-3aH-cyclopentathiazol-2-yl)-3-(4-methanesulfonylphenoxy)benzamide,3-(4-dimethylcarbamoyl-phenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(4-acetylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-3-(1,3,4-thiadiazol-2-ylsulfanyl)benzamide,N-(1-ethyl-1H-pyrazol-3-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methoxycarbonylaminomethyl-phenoxy)-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide,5-(1-hydroxymethyl-propoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-methanesulfonylpyridin-3-yloxy)-5-(1-methoxymethyl-propoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-isopropoxy-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenylsulfanyl)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-cyclopropyloxy-3-(4-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-methanesulfonylpyridin-3-yloxy)-5-(1-methoxymethyl-propoxy)-N-(pyrazol-3-yl)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(1-hydroxymethyl-propoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(6-ethanesulfonylpyridin-3-yloxy)-3-(2-methoxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,2-[3-(4-methanesulfonylphenoxy)-5-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-phenoxy]propionicacid tert-butyl ester,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-methoxy-1-methyl-ethoxy)-N-(pyrazol-3-yl)-benzamide,3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)-5-(tetrahydrofuran-3-yl)benzamide,N-(1-ethyl-1H-pyrazol-3-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(pyrazol-3-yl)benzamide,3-(6-methanesulfonylpyridin-3-yloxy)-5-(2-methoxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-fluoro-1-fluoromethyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,2-[3-(4-methanesulfonylphenoxy)-5-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-phenoxy]propionicacid,3-(6-ethanesulfonylpyridin-3-yloxy)-5-isopropoxy-N-(pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-isopropoxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(pyridin-2-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide-5-(2-fluoro-1-methyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-chloro-1-methyl-ethoxy)-3-(6-ethanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-N-(isoxazol-3-yl)-3-(6-methanesulfonylpyridin-3-yloxy)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(pyridin-2-yl)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(3-methyl-[1,2,4]-thiadiazol-5-yl)benzamide,3-(4-dimethylsulfamoylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(3-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(6-isopropylsulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(3-chloro-4-methanesulfonylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-3-(pyridin-3-yloxy)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-3-(pyridin-3-yloxy)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-3-(pyridin-4-yloxy)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-3-(pyridin-4-yloxy)benzamide,2-[3-(6-ethanesulfonylpyridin-3-yloxy)-5-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-phenoxy]propionicacid,5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(3-fluoro-4-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,or their pharmaceutically acceptable salts;

(16) The compound5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-N-thiazol-2-yl-benzamideor a pharmaceutically acceptable salt thereof;

(17) The compoundN-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methanesulfonylphenoxy)-5-(1-methoxymethyl-propoxy)-benzamideor a pharmaceutically acceptable salt thereof;

(18) The compound5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-N-pyridin-2-yl-benzamideor a pharmaceutically acceptable salt thereof;

(19) The compound5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-N-(2-methylthiazol-4-yl)-benzamideor a pharmaceutically acceptable salt thereof;

(20) The compound5-(2-hydroxy-1-methyl-ethoxy)-3-([1,3,4]thiadiazol-2-ylsulfanyl)-N-thiazol-2-yl-benzamideor a pharmaceutically acceptable salt thereof;

(21) The compound5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-N-(3-methyl-[1,2,4]-thiadiazol-5-yl)-benzamideor a pharmaceutically acceptable salt thereof;

(22) The compound5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamideor a pharmaceutically acceptable salt thereof;

(23) The compound3-(3-fluoro4-methanesulfonylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamideor a pharmaceutically acceptable salt thereof;

(24) The compound3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamideor a pharmaceutically acceptable salt thereof;

(25) The compound3-(6-ethanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-N-(1-methyl-1H-pyrazol-3-yl)benzamideor a pharmaceutically acceptable salt thereof;

(26) The compound5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonyl-pyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamideor a pharmaceutically acceptable salt thereof;

(27) The compound3-(6-ethanesulfonyl-pyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)benzamideor a pharmaceutically acceptable salt thereof;

(28) The compound5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonyl-pyridin-3-yloxy)-N-(pyrazol-3-yl)benzamideor a pharmaceutically acceptable salt thereof;

(29) Pharmaceutical compositions comprising the following (1) to (3),which are used to treat, prevent or delay onset of type II diabetes.

(1) A compound represented by formula (I),

(2) 1, 2 or more compounds selected from the group consisting of thefollowing (a) to (g):

-   -   (a) other glucokinase activators    -   (b) bisguanides    -   (c) PPAR agonists    -   (d) insulin    -   (e) somatostatin    -   (f) α-glucosidase inhibitors, and    -   (g) insulin secretagogues,

(3) a pharmaceutically acceptable carrier.

(30) Glucokinase activators comprising compounds according to any one of(1) to (28) above as active ingredients;

(31) Drugs for treatment and/or prevention of diabetes which comprisecompounds according to any one of (1) to (28) above; and

(32) Drugs for treatment and/or prevention of obesity which comprisecompounds according to any one of (1) to (28) above.

The meanings of the terms used throughout the present specification willnow be explained, and the compounds of the invention will then beexplained in greater detail.

An “aryl” group is a C6-14 hydrocarbon aryl group, examples of whichinclude phenyl, naphthyl, biphenyl and anthryl.

A “lower alkyl” group is preferably a C1-6 straight-chain or branchedalkyl group, examples of which include methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, neopentyl,isopentyl, 1,1-dimethylpropyl, 1-methylbutyl, 2-methylbutyl,1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl,1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl,2-ethylbutyl, 1,2,2-trimethylpropyl and 1-ethyl-2-methylpropyl.

A “lower alkenyl” group is a C1-6 straight-chain or branched loweralkenyl group, examples of which include vinyl, allyl, 1-butenyl,2-butenyl and 1-pentenyl.

An “alkoxy” group is a group wherein the hydrogen of hydroxyl has beensubstituted with the aforementioned lower alkyl group, and examplesthereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy,sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy andisohexyloxy.

A “heteroaryl” group is a 5- to 7-membered monocyclic group having inthe heteroaryl group 1 to 3 hetero atoms selected from the groupconsisting of oxygen, sulfur and nitrogen atoms, or a bicyclicheteroaryl group comprising such a monocyclic heteroaryl group fusedwith a benzene ring or pyridine ring, and examples thereof includefuryl, thienyl, pyrrolyl, imidazolyl, triazolyl, thiazolyl,thiadiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl,pyridazinyl, pyrazolyl, pyrazinyl, quinolyl, isoquinolyl, quinazolinyl,quinolidinyl, quinoxalinyl, cinnolinyl, benzimidazolyl, imidazopyridyl,benzofuranyl, naphthylidinyl, 1,2-benzoisoxazolyl, benzooxazolyl,benzothiazolyl, oxazolopyridyl, pyridothiazolyl, isothiazolopyridyl andbenzothienyl.

A “halogen atom” is, for example, fluorine, chlorine, bromine, iodine,or the like.

A “hydroxyalkyl” group is a group wherein one hydrogen of theaforementioned lower alkyl group is substituted with hydroxy, andexamples thereof include hydroxymethyl, hydroxyethyl, 1-hydroxypropyl,1-hydroxyethyl, 2-hydroxypropyl and 2-hydroxy-1-methyl-ethyl.

An “alkylcarbamoyl” group is a carbamoyl group monosubstituted with theaforementioned lower alkyl, and examples thereof includemethylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl,butylcarbamoyl, sec-butylcarbamoyl and tert-butylcarbamoyl.

A “dialkylcarbamoyl” group is a carbamoyl group disubstituted withidentical or different lower alkyl groups, and examples of“dialkylcarbamoyl” groups include dimethylcarbamoyl, diethylcarbamoyl,ethylmethylcarbamoyl, dipropylcarbamoyl, methylpropylcarbamoyl anddiisopropylcarbamoyl.

An “alkylamino” group is an amino group monosubstituted with theaforementioned lower alkyl group, and examples thereof includemethylamino, ethylamino, propylamino, isopropylamino, butylamino,sec-butylamino and tert-butylamino.

A “dialkylamino” group is an amino group disubstituted with identical ordifferent lower alkyl groups, and examples thereof includedimethylamino, diethylamino, dipropylamino, methylpropylamino anddiisopropylamino.

An “aminoalkyl” group is a group wherein one hydrogen of theaforementioned alkyl group is substituted with an amino group, andexamples thereof include aminomethyl, aminoethyl and aminopropyl.

An “alkanoyl” group is a group wherein the aforementioned alkyl group isbonded with a carbonyl group, and examples thereof includemethylcarbonyl, ethylcarbonyl, propylcarbonyl and isopropylcarbonyl.

An “alkanoylamino” group is a group wherein the aforementioned alkanoylgroup is bonded with an amino group, and examples thereof includemethylcarbonylamino, ethylcarbonylamino and isopropylcarbonylamino.

An “alkanoylaminoalkyl” group is a group wherein one hydrogen of theaforementioned alkyl group is substituted with the aforementionedalkanoylamino group, and examples thereof include acetylaminomethyl,ethylcarbonylaminomethyl, methylcarbonylaminoethyl andisopropylcarbonylaminomethyl.

An “alkylthio” group is a group wherein the aforementioned alkyl groupis bonded with a sulfur atom, and examples thereof include methylthio,ethylthio, propylthio and isopropylthio.

An “alkylsulfonyl” group is a group wherein the aforementioned alkylgroup is bonded with a sulfonyl group, and examples thereof includemethylsulfonyl, ethylsulfonyl, propylsulfonyl and isopropylsulfonyl.

An “alkylsulfonylamino” group is a group wherein one hydrogen of anamino group is monosubstituted with the aforementioned alkylsulfonylgroup, and examples thereof include methylsulfonylamino,ethylsulfonylamino, propylsulfonylamino and isopropylsulfonylamino.

An “alkoxycarbonyl” group is a group wherein the hydrogen of a carboxylgroup is substituted with the aforementioned alkyl group, and examplesthereof include methoxycarbonyl, ethoxycarbonyl, propylcarbonyl andisopropylcarbonyl.

An “alkoxycarbonylamino” group is a group wherein one hydrogen of anamino group is substituted with the aforementioned alkoxycarbonyl group,and examples thereof include methoxycarbonylamino, ethoxycarbonylamino,propylcarbonylamino and isopropylcarbonylamino.

An “alkoxycarbonylaminoalkyl” group is a group wherein one hydrogen ofthe aforementioned alkyl group is substituted with the aforementionedalkoxycarbonylamino group, and examples thereof includemethoxycarbonylaminomethyl, ethoxycarbonylaminomethyl andisopropylcarbonylaminoethyl.

An “alkylsulfamoyl” group is a group wherein one hydrogen of the NH₂ ofa sulfamoyl group is substituted with the aforementioned lower alkylgroup, and examples thereof include methylsulfamoyl, ethylsulfamoyl andisopropylsulfamoyl.

A “dialkylsulfamoyl” group is a group wherein the two hydrogens of NH₂of a sulfamoyl group are substituted with identical or different loweralkyl groups, and examples thereof include dimethylsulfamoyl,diethylsulfamoyl, ethylmethylsulfamoyl and diisopropylsulfamoyl.

For a more detailed disclosure of the compounds represented by formula(I) above of the present invention, each of the symbols used in formula(I) will be explained using specific examples.

Formula (II):

represents a 6- to 10-membered aryl group or 5- to 7-membered heteroarylgroup optionally having on the ring 1 or 2 substituents represented byR¹ above.

As examples of “6- to 10-membered aryl” groups represented by Ring Athere may be mentioned phenyl and naphthyl, among which phenyl ispreferred.

As “5- to 7-membered heteroaryl” groups represented by Ring A there maybe mentioned the “5- to 7-membered heteroaryl” groups for the“heteroaryl” groups defined above, and 5- to 6-membered heteroarylgroups are preferred.

As examples of “5- to 7-membered heteroaryl” groups represented by RingA there are preferred furyl, thienyl, pyrrolyl, imidazolyl, triazolyl,pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, isoxazolyl,pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl, among which triazolyl,thiazolyl, thiadiazolyl, pyridyl and pyrazinyl are more preferred, andtriazolyl, thiadiazolyl and pyridyl are even more preferred.

Preferred as Ring A are thiadiazolyl, phenyl and pyridyl, with phenyland pyridyl being more preferred.

Ring A optionally has on the ring 1 or 2 substituents represented by R¹.Here, R¹ represents a group selected from among alkylsulfonyl, alkanoyl,alkyl, hydroxyalkyl, hydroxy, alkylcarbamoyl, alkylsulfamoyl,dialkylsulfamoyl, alkylthio, alkoxy, dialkylcarbamoyl,alkoxycarbonylamino, halogen atoms, cyano, alkoxycarbonyl,alkanoylaminoalkyl, alkylsulfonylaminoalkyl, alkoxycarbonylaminoalkyland trifluoromethyl, and when Ring A has two such substituents, thesubstituents may be the same or different.

As groups for R¹ there are preferred alkylsulfonyl, alkanoyl,hydroxyalkyl, alkylcarbamoyl, alkylsulfamoyl, dialkylsulfamoyl,dialkylcarbamoyl, alkoxycarbonylamino, halogen atoms,alkanoylaminoalkyl, alkylsulfonylaminoalkyl andalkoxycarbonylaminoalkyl, with alkylsulfonyl, alkanoyl, hydroxyalkyl,halogen atoms, alkanoylaminoalkyl, alkylsulfonylaminoalkyl andalkoxycarbonylaminoalkyl being more preferred, alkylsulfonyl, alkanoyl,halogen atoms and hydroxyalkyl being even more preferred, andalkylsulfonyl being especially preferred.

When Ring A has an R¹ group on the ring, the position at which R¹ isbonded on Ring A is not particularly restricted, and may be any bondableposition.

When Ring A is phenyl, the bonding position of R¹ on the phenyl group ispreferably the para position with respect to the bond between X¹ and thephenyl group.

X¹ represents O, S or NH, among which O or S is preferred, and O is morepreferred.

Thus, as specific examples of —X¹-Ring A-R¹ when X¹ is O and Ring A isphenyl, there may be mentioned 4-(1-hydroxyethyl)-phenoxy,4-(1-hydroxypropyl)-phenoxy, 4-methanesulfonylphenoxy,4-methylcarbonyl-phenoxy, 4-methylcarbamoyl-phenoxy,4-ethylcarbonyl-phenoxy, 4-dimethylcarbamoyl-phenoxy,4-methylcarbonylaminomethyl-phenoxy,4-methanesulfonylaminomethyl-phenoxy,4-methoxycarbonylaminomethyl-phenoxy, 2-fluoro-phenoxy,4-methoxycarbonyl-phenoxy, 4-hydroxymethyl-phenoxy,4-methanesulfonyl-2-fluoro-phenoxy, ⁴-cyano-phenoxy, 4-methyl-phenyloxy,4-trifluoromethyl-phenyloxy, 3-fluoro-4-methanesulfonylphenoxy,4-dimethylsulfamoylphenoxy, 3-chloro-4-methanesulfonylphenoxy and3-methanesulfonylphenoxy, among which 4-(1-hydroxyethyl)-phenoxy,4-(1-hydroxypropyl)-phenoxy, 4-methanesulfonylphenoxy,4-methylcarbonyl-phenoxy, 4-methylcarbamoyl-phenoxy,4-ethylcarbonyl-phenoxy, 4-dimethylcarbamoyl-phenoxy,4-methylcarbonylaminomethyl-phenoxy,4-methanesulfonylaminomethyl-phenoxy,4-methoxycarbonylaminomethyl-phenoxy, 4-hydroxymethyl-phenoxy,4-methanesulfonyl-2-fluoro-phenoxy, 3-fluoro-4-methanesulfonylphenoxy,4-dimethylsulfamoylphenoxy and 3-chloro-4-methanesulfonylphenoxy arepreferred, 4-(1-hydroxyethyl)-phenoxy, 4-(1-hydroxypropyl)-phenoxy,4-methanesulfonylphenoxy, 4-methylcarbonyl-phenoxy,4-ethylcarbonyl-phenoxy, 4-methylcarbonylaminomethyl-phenoxy,4-methanesulfonylaminomethyl-phenoxy,4-methoxycarbonylaminomethyl-phenoxy, 4-hydroxymethyl-phenoxy,3-fluoro4-methanesulfonylphenoxy, 4-dimethylsulfamoylphenoxy and3-chloro-4-methanesulfonylphenoxy are more preferred,4-(1-hydroxyethyl)-phenoxy, 4-(1-hydroxypropyl)-phenoxy,4-methanesulfonylphenoxy, 4-methylcarbonyl-phenoxy,4-ethylcarbonyl-phenoxy, 4-hydroxymethyl-phenoxy and3-fluoro-4-methanesulfonylphenoxy are even more preferred, and4-methanesulfonylphenoxy is especially preferred.

As specific examples of —X¹-Ring A-R¹— when X¹ is S and Ring A isphenyl, there may be mentioned 4-fluoro-phenylsulfanyl,4-methyl-phenylsulfanyl, 4-trifluoromethyl-phenylsulfanyl,4-(1-hydroxyethyl)-phenylsulfanyl, 4-methanesulfonylphenylsulfanyl,4-methylcarbonyl-phenylsulfanyl, 4-ethylcarbonyl-phenylsulfanyl,4-methylcarbamoyl-phenylsulfanyl, 4-dimethylcarbamoyl-phenylsulfanyl,4-methylcarbonylaminomethyl-phenylsulfanyl,4-methylsulfonylaminomethyl-phenylsulfanyl,4-methoxycarbonyl-phenylsulfanyl,4-methoxycarbonyl-aminomethyl-phenylsulfanyl,4-hydroxymethyl-phenylsulfanyl and 4-cyano-phenylsulfanyl, among which4-fluoro-phenylsulfanyl, 4-(1-hydroxyethyl)-phenylsulfanyl,4-methanesulfonylphenylsulfanyl, 4-methylcarbonyl-phenylsulfanyl,4-ethylcarbonyl-phenylsulfanyl, 4-methylcarbamoyl-phenylsulfanyl,4-dimethylcarbamoyl-phenylsulfanyl,4-methylcarbonylaminomethyl-phenylsulfanyl,4-methylsulfonylaminomethyl-phenylsulfanyl,4-methoxycarbonyl-aminomethyl-phenylsulfanyl and4-hydroxymethyl-phenylsulfanyl are preferred,4-(1-hydroxyethyl)-phenylsulfanyl, 4-methanesulfonylphenylsulfanyl,4-methylcarbonyl-phenylsulfanyl, 4-ethylcarbonyl-phenylsulfanyl,4-methylcarbonylaminomethyl-phenylsulfanyl,4-methylsulfonylaminomethyl-phenylsulfanyl,4-methoxycarbonyl-aminomethyl-phenylsulfanyl and4-hydroxymethyl-phenylsulfanyl are more preferred,4-(1-hydroxyethyl)-phenylsulfanyl, 4-methanesulfonylphenylsulfanyl,4-methylcarbonyl-phenylsulfanyl, 4-ethylcarbonyl-phenylsulfanyl and4-hydroxymethyl-phenylsulfanyl are even more preferred, and4-methanesulfonylphenylsulfanyl is especially preferred.

As specific examples of —X¹-Ring A-R¹— when X¹ is S and Ring A is a 5-to 7-membered heteroaryl group, there may be mentioned5-cyano-pyridin-2-ylsulfanyl, 5-bromo-pyridin-2-ylsulfanyl,5-methoxycarbonyl-pyridin-2-ylsulfanyl,5-hydroxymethyl-pyridin-2-ylsulfanyl,5-methanesulfonylpyridin-2-ylsulfanyl, 5-methyl-pyridin-2-ylsulfanyl,5-trifluoromethyl-pyridin-2-ylsulfanyl, pyridine-2-ylsulfanyl,pyridin-4-ylsulfanyl, 6-methyl-pyridin-3-ylsulfanyl,[1,3,4]thiadiazol-2-ylsulfanyl,5-methylthio-[1,3,4]thiadiazol-2-ylsulfanyl,5-methanesulfonyl[1,3,4]thiadiazol-2-ylsulfanyl,[1,2,4]-triazol-3-ylsulfanyl, furan-3-ylsulfanyl, thiophen-3-ylsulfanyl,pyrrol-3-ylsulfanyl, imidazol-2-ylsulfanyl, thiazol-2-ylsulfanyl,oxazol-2-ylsulfanyl, isoxazol-3-ylsulfanyl, pyrazin-2-ylsulfanyl,pyrimidin-2-ylsulfanyl, pyridazin-3-ylsulfanyl and3H-pyrazol-3-ylsulfanyl, among which 5-bromo-pyridin-2-ylsulfanyl,5-hydroxymethyl-pyridin-2-ylsulfanyl,5-methanesulfonylpyridin-2-ylsulfanyl, pyridine-2-ylsulfanyl,pyridin-4-ylsulfanyl, [1,3,4]thiadiazol-2-ylsulfanyl,5-methanesulfonyl[1,3,4]thiadiazol-2-ylsulfanyl,[1,2,4]-triazol-3-ylsulfanyl, furan-3-ylsulfanyl, thiophen-3-ylsulfanyl,pyrrol-3-ylsulfanyl, imidazol-2-ylsulfanyl, thiazol-2-ylsulfanyl,oxazol-2-ylsulfanyl, isoxazol-3-ylsulfanyl, pyrazin-2-ylsulfanyl,pyrimidin-2-ylsulfanyl, pyridazin-3-ylsulfanyl and3H-pyrazol-3-ylsulfanyl are preferred,5-hydroxymethyl-pyridin-2-ylsulfanyl,5-methanesulfonylpyridin-2-ylsulfanyl, pyridine-2-ylsulfanyl,pyridin-4-ylsulfanyl, [1,3,4]thiadiazol-2-ylsulfanyl,5-methanesulfonyl[1,3,4]thiadiazol-2-ylsulfanyl,[1,2,4]-triazol-3-ylsulfanyl, thiazol-2-ylsulfanyl andpyrazin-2-ylsulfanyl are more preferred,5-hydroxymethyl-pyridin-2-ylsulfanyl,5-methanesulfonylpyridin-2-ylsulfanyl, pyridine-2-ylsulfanyl,pyridin-4-ylsulfanyl, [1,3,4]thiadiazol-2-ylsulfanyl,5-methanesulfonyl[1,3,4]thiadiazol-2-ylsulfanyl,[1,2,4]-triazol-3-ylsulfanyl and thiazol-2-ylsulfanyl are even morepreferred, and pyridine-2-ylsulfanyl, pyridin-4-ylsulfanyl,[1,3,4]thiadiazol-2-ylsulfanyl, [1,2,4]-triazol-3-ylsulfanyl andthiazol-2-ylsulfanyl are especially preferred.

As specific examples of —X¹-Ring A-R¹ when X¹ is O and Ring A is a 5- to7-membered heteroaryl group, there may be mentioned pyrimidin-4-yloxy,pyridazin-3-yloxy, pyrazin-2-yloxy, pyridin-2-yloxy,2-hydroxy-pyridin-3-yloxy, 2-hydroxy-pyridin-4-yloxy,5-hydroxymethyl-pyridin-2-yloxy, 5-methylcarbonyl-pyridin-2-yloxy,5-(1-hydroxyethyl)-pyridin-2-yloxy,5-methoxycarbonylaminomethyl-pyridin-2-yloxy,5-methanesulfonylpyridin-2-yloxy, 5-methoxycarbonyl-pyridin-2-yloxy,5-cyano-pyridin-2-yloxy, 5-bromo-pyridine-2-yloxy,5-dimethylcarbamoyl-pyridin-2-yloxy, 5-methoxycarbonyl-pyridin-2-yloxy,5-methylcarbonylaminomethyl-pyridin-2-yloxy,5-trifluoromethyl-pyridin-2-yloxy, 5-methylcarbonyl-imidazol-2-yloxy,6-hydroxymethyl-pyrimidin-2-yloxy, 6-methylcarbonyl-pyrimidin-2-yloxy,6-methanesulfonylpyrimidin-2-yloxy, 6-hydroxymethyl-pyridazin-3-yloxy,6-methylcarbonyl-pyridazin-3-yloxy, 6-methanesulfonylpyridazin-3-yloxy,5-hydroxymethyl-pyrazin-2-yloxy, 5-methylcarbonyl-pyrazin-2-yloxy,5-methanesulfonylpyrazin-2-yloxy, 6-ethanesulfonylpyridin-3-yloxy,6-methanesulfonylpyridin-3-yloxy, pyridin-3-yloxy, pyridin-4-yloxy and6-isopropylsulfonylpyridin-3-yloxy, among which pyrimidin-4-yloxy,pyridazin-3-yloxy, pyrazin-2-yloxy, pyridin-2-yloxy,2-hydroxy-pyridin-3-yloxy, 2-hydroxy-pyridin-4-yloxy,5-hydroxymethyl-pyridin-2-yloxy, 5-methylcarbonyl-pyridin-2-yloxy,5-(1-hydroxyethyl)-pyridin-2-yloxy,5-methoxycarbonylaminomethyl-pyridin-2-yloxy,5-methanesulfonylpyridin-2-yloxy, 5-bromo-pyridine-2-yloxy,5-dimethylcarbamoyl-pyridin-2-yloxy,5-methylcarbonylaminomethyl-pyridin-2-yloxy,5-methylcarbonyl-imidazol-2-yloxy, 6-hydroxymethyl-pyrimidin-2-yloxy,6-methylcarbonyl-pyrimidin-2-yloxy, 6-methanesulfonylpyrimidin-2-yloxy,6-hydroxymethyl-pyridazin-3-yloxy, 6-methylcarbonyl-pyridazin-3-yloxy,6-methanesulfonylpyridazin-3-yloxy, 5-hydroxymethyl-pyrazin-2-yloxy,5-methylcarbonyl-pyrazin-2-yloxy, 5-methanesulfonylpyrazin-2-yloxy,6-ethanesulfonylpyridin-3-yloxy, 6-methanesulfonylpyridin-3-yloxy,pyridin-3-yloxy and pyridin-4-yloxy are preferred, pyrazin-2-yloxy,pyridin-2-yloxy, 2-hydroxy-pyridin-3-yloxy, 2-hydroxy-pyridin-4-yloxy,5-hydroxymethyl-pyridin-2-yloxy, 5-methylcarbonyl-pyridin-2-yloxy,5-(1-hydroxyethyl)-pyridin-2-yloxy,5-methoxycarbonylaminomethyl-pyridin-2-yloxy,5-methanesulfonylpyridin-2-yloxy,5-methylcarbonylaminomethyl-pyridin-2-yloxy,5-hydroxymethyl-pyrazin-2-yloxy, 5-methylcarbonyl-pyrazin-2-yloxy,5-methanesulfonylpyrazin-2-yloxy, 6-ethanesulfonylpyridin-3-yloxy and6-methanesulfonylpyridin-3-yloxy are more preferred, and2-hydroxy-pyridin-3-yloxy, 2-hydroxy-pyridin-4-yloxy,5-hydroxymethyl-pyridin-2-yloxy, 5-methylcarbonyl-pyridin-2-yloxy,5-(1-hydroxyethyl)-pyridin-2-yloxy or 5-methanesulfonylpyridin-2-yloxy,6-methanesulfonylpyridin-3-yloxy and 6-ethanesulfonylpyridin-3-yloxy areespecially preferred.

X² represents O, S or CH₂, among which O and CH₂ are preferred, and O ismore preferred.

R² represents a C3-7 cyclic alkyl group, a straight-chain or branchedlower alkyl group or a lower alkenyl group, optionally having 1 or 2substituents selected from the group consisting of halogen atoms,carboxyl, alkoxycarbonyl, hydroxy, amino (where the amino may be furthersubstituted with 1 or 2 alkanoyl or lower alkyl groups), alkoxy andN-alkylcarbamoyl.

As “halogen atoms” represented by R² there may be mentioned the sameones referred to above. Chlorine and fluorine are preferred.

An “alkoxycarbonyl” group represented by R² is a carbonyl group havingan alkoxy group as defined above, and as examples there may be mentionedmethoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyland tert-butyloxycarbonyl.

As examples of the “C3-7 cyclic alkyl group” represented by R² there maybe mentioned cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl, among which cyclopentyl or cyclohexyl are preferred, andcyclopentyl is more preferred.

When R² is a C3-7 cyclic alkyl group, any one of the carbon atomsforming the ring, other than the carbon atom bonding with X², may bereplaced with oxygen, NH, N-alkanoyl or CONH.

As groups wherein “a carbon atom forming the C3-7 cyclic alkyl group(other than the carbon atom bonding with X²) is replaced with oxygen,NH, N-alkanoyl or CONH”, there are preferred groups wherein the carbonatom is replaced with oxygen, NH or N-alkanoyl, and more preferablygroups wherein it is replaced with oxygen or N-alkanoyl. Morespecifically, R² is preferably, for example, tetrahydrofuranyl,tetrahydropyranyl, pyrrolidinyl, piperidinyl or N-acetylpiperidinyl, andeven more preferably tetrahydrofuranyl, tetrahydropyranyl orN-acetylpiperidinyl.

A “straight-chain or branched lower alkyl group” represented by R² is alower alkyl having the same meaning as defined above. As lower alkylgroups there are preferred ethyl, propyl, isopropyl, butyl, isobutyl andsec-butyl, with propyl, isopropyl, isobutyl and sec-butyl being morepreferred.

As a “lower alkenyl group” represented by R² there may be mentioned thesame ones as defined above, among which propenyl, isopropenyl andisobutenyl are preferred, and isopropenyl is more preferred.

R² is preferably a C3-7 cyclic alkyl group, a straight-chain or branchedlower alkyl group, or a group wherein a carbon atom forming the C3-7cyclic alkyl group (other than the carbon atom bonding with X²) isreplaced with oxygen, NH, N-alkanoyl or CONH, and it is more preferablya straight-chain or branched lower alkyl group or a group wherein acarbon atom forming the C3-7 cyclic alkyl group (other than the carbonatom bonding with X²) is replaced with oxygen, NH, N-alkanoyl or CONH.

Therefore, as examples of —X²—R² there may be mentioned propyl,isobutyl, sec-butyl, 3-methoxy-2-methyl-propyl, 2-methoxymethyl-butyl,4-hydroxy-2-methyl-butyl, 2-hydroxymethyl-butyl, 3-hydroxy-butyl,3-methoxybutyl, 3-hydroxy-2-methyl-propyl, 3-hydroxy-butyl,3-methylcarbamoyl-propyl, 3-acetylamino-2-methyl-propyl,2-hydroxymethyl-3-propenyl, 2-methyl-2-propenyl, ethoxy, isopropoxy,2-methoxy-1-methyl-ethoxy, 1-methoxymethyl-propoxy,3-hydroxy-1-methyl-propoxy, 1-hydroxymethyl-propoxy, 2-amino-1-ethoxy,2-hydroxy-propoxy, 2-methoxypropoxy, 2-hydroxy-1-methyl-ethoxy,2-hydroxy-ethoxy, 2-dimethylamino-1-methyl-ethoxy, 1-carboxy-ethoxy,2-methylcarbamoyl-ethoxy, 2-acetylamino-1-methyl-ethoxy, cyclopentyloxy,cyclohexyloxy, cycloheptyloxy, 2-hydroxy-cyclopentyloxy,tetrahydrofuran-3-yloxy, tetrahydrofuran-2-yloxy,tetrahydrofuran-4-yloxy, piperidin-4-yloxy, piperidin-3-yloxy,pyrrolidin-3-yloxy, pyrrolidin-2-yloxy, 1-acetyl-piperidin-4-yloxy,1-acetyl-piperidin-3-yloxy, 3-allyloxy, 3-isopropenyloxy,1-methyl-allyloxy, 2-fluoro-1-fluoromethyl-ethoxy,2-fluoro-1-methyl-ethoxy and 2-chloro-1-methyl-ethoxy, among whichethoxy, isopropoxy, 2-methoxy-1-methyl-ethoxy, 1-methoxymethyl-propoxy,3-hydroxy-1-methyl-propoxy, 1-hydroxymethyl-propoxy, 2-hydroxy-propoxy,2-methoxypropoxy, 2-hydroxy-1-methyl-ethoxy, 2-hydroxy-ethoxy,2-methylcarbamoyl-ethoxy, 2-acetylamino-1-methyl-ethoxy, cyclopentyloxy,cyclohexyloxy, 2-hydroxy-cyclopentyloxy, tetrahydrofuran-3-yloxy,tetrahydrofuran-2-yloxy, tetrahydropyran-3-yloxy,tetrahydrofuran-4-yloxy, piperidin-4-yloxy, piperidin-3-yloxy,pyrrolidin-3-yloxy, pyrrolidin-2-yloxy, 1-acetyl-piperidin-4-yloxy,1-acetyl-piperidin-3-yloxy, 3-isopropenyloxy, 1-methyl-allyloxy, butyl,isobutyl, s-butyl, 3-methoxy-2-methyl-propyl, 2-methoxymethyl-butyl,4-hydroxy-2-methyl-butyl, 2-hydroxymethyl-butyl, 3-hydroxy-butyl,3-methoxybutyl, 3-hydroxy-2-methyl-propyl, 3-hydroxy-butyl,3-methylcarbamoyl-propyl, 3-acetylamino-2-methyl-propyl,2-hydroxymethyl-3-propenyl, 2-methyl-2-propenyl,2-fluoro-1-fluoromethyl-ethoxy, 2-fluoro-1-methyl-ethoxy and2-chloro-1-methyl-ethoxy are preferred, 2-methoxy-1-methyl-ethoxy,1-methoxymethyl-propoxy, 3-hydroxy-1-methyl-propoxy,1-hydroxymethyl-propoxy, 2-hydroxy-propoxy, 2-methoxypropoxy,2-hydroxy-1-methyl-ethoxy, 2-hydroxy-ethoxy, 2-methylcarbamoyl-ethoxy,2-acetylamino-1-methyl-ethoxy, cyclopentyloxy, cyclohexyloxy,2-hydroxy-cyclopentyloxy, tetrahydrofuran-3-yloxy,tetrahydropyran-3-yloxy, 1-acetyl-piperidin-4-yloxy,1-acetyl-piperidin-3-yloxy, 3-isopropenyloxy, 3-methoxy-2-methyl-propyl,2-methoxymethyl-butyl, 4-hydroxy-2-methyl-butyl, 2-hydroxymethyl-butyl,3-hydroxy-butyl, 3-methoxybutyl, 3-hydroxy-2-methyl-propyl,3-hydroxy-butyl, 3-methylcarbamoyl-propyl,3-acetylamino-2-methyl-propyl, 2-hydroxymethyl-3-propenyl,2-methyl-2-propenyl, 2-fluoro-1-fluoromethyl-ethoxy and2-fluoro-1-methyl-ethoxy are more preferred, and2-methoxy-1-methyl-ethoxy, 1-methoxymethyl-propoxy,3-hydroxy-1-methyl-propoxy, 1-hydroxymethyl-propoxy,2-hydroxy-1-methyl-ethoxy, 2-acetylamino-1-methyl-ethoxy,2-hydroxy-cyclopentyloxy, tetrahydrofuran-3-yloxy,1-acetyl-piperidin-4-yloxy, 3-methoxy-2-methyl-propyl,2-methoxymethyl-butyl, 4-hydroxy-2-methyl-butyl, 2-hydroxymethyl-butyl,3-hydroxy-2-methyl-propyl, 3-acetylamino-2-methyl-propyl,2-hydroxymethyl-3-propenyl and 2-fluoro-1-fluoromethyl-ethoxy areespecially preferred.

Ring B is a group represented by the aforementioned formula (III):

which is a monocyclic or bicyclic heteroaryl group wherein the carbonatom of Ring B which is bonded to the nitrogen atom of the amide groupof formula (I) forms a C═N bond with the nitrogen atom of the ring.

Here, a “heteroaryl” group represented by Ring B is a “heteroaryl” grouprepresented by formula (E) and as defined above, wherein the carbon atomof Ring B which is bonded to the amide group in formula (I) forms a C═Nbond with the nitrogen atom. The double bond of C═N in Ring B is only aformal representation, and it is sufficient if Ring B is a heteroarylgroup.

Preferred examples of Ring B are those wherein the heteroaryl group doesnot include a 5-alkoxycarbonyl-pyridin-2-yl or 5-carboxyl-pyridin-2-ylgroup, and more preferred are monocyclic or bicyclic heteroaryl groupshaving at least one hetero atom in Ring B selected from the groupconsisting of nitrogen, sulfur and oxygen atoms, in addition to thenitrogen atom forming the C═N group together with the carbon atom in thering which is bonded to the nitrogen atom of the amide group in formula(I) above.

Ring B is a monocyclic or bicyclic heteroaryl group having at least onehetero atom in Ring B selected from the group consisting of nitrogen,sulfur and oxygen atoms, in addition to the nitrogen atom forming theC═N group together with the carbon atom in Ring B which is bonded to thenitrogen atom of the amide group in formula (I) above, and when Ring Bis a thiazole group, the substituent at the 5-position of the thiazolegroup is most preferably not isopropyl.

When Ring B is a monocycle, the number of atoms forming the monocycle ispreferably 5 or 6, and more preferably 5. When Ring B is a bicycle, itis preferably a 9- to 10-membered bicycle which is a 5- or 6-memberedmonocycle fused with a benzene ring or pyridine ring, and it is morepreferably a 9-membered bicycle which is a 5-membered monocycle fusedwith a pyridine ring.

As specific examples for Ring B there may be mentioned thiazolyl,imidazolyl, isothiazolyl, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl,pyrazinyl, pyridyl, pyridazinyl, pyrazolyl, pyrimidinyl, pyridothiazolyland benzothiazolyl, among which thiazolyl, thiadiazolyl, isoxazolyl,pyrazinyl, pyridyl, pyridothiazolyl and pyrazolyl are preferred, andthiazolyl, thiadiazolyl, isoxazolyl, pyridothiazolyl or pyrazolyl aremore preferred.

Ring B may have 1 or 2 substituents represented by R³. Here, R³represents a group selected from among lower alkyl, alkoxy, alkylamino,lower dialkylamino, halogen atoms, trifluoromethyl, hydroxyalkyl(wherein the hydrogen of the hydroxy in the hydroxyalkyl group may besubstituted with lower alkyl), aminoalkyl, alkanoyl, carboxyl,alkoxycarbonyl and cyano.

When Ring B has two R³ substituents in the ring, they may be identicalor different.

The bonding position of R³ on Ring B may be any bondable position onRing B, with no particular restrictions, regardless of whether Ring B isa 5- to 7-membered monocyclic heteroaryl group or a 9- to 11-memberedbicyclic heteroaryl group.

Among these, R³ is preferably lower alkyl, alkoxy, a halogen,hydroxyalkyl (where the hydrogen of the hydroxy in the hydroxyalkylgroup may be substituted with lower alkyl), aminoalkyl or alkanoyl, andit is more preferably lower alkyl, hydroxyalkyl (where the hydrogen ofthe hydroxy in the hydroxyalkyl group may be substituted with loweralkyl) or alkanoyl.

As specific examples for R³ there may be mentioned methyl, ethyl,propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy,chlorine, fluorine, bromine, hydroxymethyl, hydroxyethyl, methoxymethyl,ethoxyethyl, methoxyethyl, methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, aminomethyl, aminoethyl, aminopropyl, methylcarbonyl,ethylcarbonyl and propylcarbonyl, among which methyl, ethyl, chlorine,fluorine, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl,methoxycarbonyl, ethoxycarbonyl, aminomethyl, aminoethyl, methylcarbonyland ethylcarbonyl are preferred, and methyl, hydroxymethyl,methoxymethyl and methylcarbonyl are more preferred.

Therefore, as specific examples of groups represented by the followingformula (VI):

[wherein the symbols have the same definitions specified above] thereare preferred thiazol-2-yl, 4-methyl-thiazol-2-yl,4-hydroxymethyl-thiazol-2-yl, 4-methoxycarbonyl-thiazol-2-yl,4-methoxymethyl-thiazol-2-yl, 4-aminomethyl-thiazol-2-yl,4-cyano-thiazol-2-yl, 4-cyano-thiazol-2-yl, 4-fluoro-thiazol-2-yl,imidazol-2-yl, 4-methyl-imidazol-2-yl, 4-methoxycarbonyl-imidazol-2-yl,isothiazol-3-yl, 4-hydroxymethyl-isothiazol-3-yl,[1,3,4]thiadiazol-2-yl, 5-acetyl-[1,3,4]thiadiazol-2-yl,[1,2,4]triazol-2-yl, 5-hydroxymethyl-[1,2,4]triazol-3-yl, pyrazin-2-yl,pyridin-2-yl, 4-methyl-pyridin-2-yl, 4-methoxymethyl-imidazol-2-yl,4-acetyl-imidazol-2-yl, 5-hydroxymethyl-imidazol-2-yl,5-methyl-[1,3,4]thiadiazol-2-yl, 5-fluoro-[1,3,4]thiadiazol-2-yl,5-methyl-[1,2,4]triazol-2-yl, 5-acetyl-[1,2,4]triazol-3-yl,4-methoxymethyl-isoxazol-2-yl, 5-methyl-isoxazol-3-yl,5-hydroxymethyl-isoxazol-3-yl, 5-methoxymethyl-isoxazol-3-yl,5-methylcarbonyl-isoxazol-3-yl, 5-chloro-isoxazol-3-yl,5-aminomethyl-isoxazol-3-yl, pyrazol-3-yl, 4-methyl-1H-pyrazol-3-yl,6-methyl-pyridazin-3-yl, thiazol-4-yl, 2-methyl-thiazol-4-yl,isoxazol-3-yl, thiazolo[5,4-b]pyridin-2-yl,3-methyl-[1,2,4]thiadiazolyl-5-yl and 1-methyl-1H-pyrazol-3-yl.

Thus, as more specific examples of compounds represented by formula (I)according to the present invention:

[wherein the symbols have the same definitions specified above] theremay be mentioned5-isopropoxy-3-(4-methanesulfonylphenoxy)-N-(4-methylthiazol-2-yl)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,5-ethoxy-3-(4-methanesulfonylphenoxy)-N-(4-methoxymethyl-thiazol-2-yl)benzamide,5-cyclopentyloxy-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,3-(4-methanesulfonylphenoxy)-5-(tetrahydrofuran-3-yloxy)-N-thiazol-2-yl-benzamide,3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide,3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methoxymethyl-ethoxy)-N-thiazol-2-yl-benzamide,3-(2-fluoro-4-methanesulfonylphenoxy)-5-isopropoxy-N-thiazol-2-yl-benzamide,3-(4-methanesulfonylphenoxy)-5-(1-methoxymethyl-propoxy)-N-(4-methyl-thiazol-2-yl)-benzamide,5-isopropoxy-3-(4-methanesulfonylphenoxy)-N-pyrazol-3-yl-benzamide,5-isopropoxy-3-(4-methanesulfonylphenoxy)-N-pyrazin-2-yl-benzamide,3-(4-methanesulfonylphenoxy)-5-(3-methoxy-1-methyl-propoxy)-N-thiazol-2-yl-benzamide,5-(3-hydroxy-1-methyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(4-methanesulfonylphenoxy)-N-pyrimidin-4-yl-benzamide,5-isopropoxy-3-(4-methanesulfonylphenoxy)-N-(pyrimidin-2-yl)-benzamide,N-(4-hydroxymethyl-thiazol-2-yl)-5-isopropoxy-3-(4-methanesulfonylphenoxy)-benzamide,N-(isooxazol-3-yl)-3-(4-methanesulfonylphenoxy)-5-(1-methoxymethyl-propoxy)-benzamide,3-(4-methanesulfonylphenoxy)-5-(1-methoxymethyl-propoxy)-N-[1,3,4]thiadiazol-2-yl-benzamide,5-(1-hydroxymethyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-(4-methyl-thiazol-2-yl)-benzamide,N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methanesulfonylphenoxy)-5-(1-methoxymethyl-propoxy)-benzamide,5-(2-amino-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,5-(2-dimethylamino-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-propoxy)-3-(4-methanesulfonylphenoxy)-N-(4-methyl-thiazol-2-yl)-benzamide,3-(4-methanesulfonylphenoxy)-5-(2-methoxy-propoxy)-N-(4-methyl-thiazol-2-yl)-benzamide,5-isopropoxy-3-(4-methanesulfonylphenoxy)-N-(thiazolo[5,4-b]pyridin-2-yl)-benzamide,5-(2-hydroxymethyl-allyl)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazolo[5,4-b]pyridin-2-yl-benzamide,5-(3-hydroxy-2-methyl-propyl)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,3-(4-methanesulfonylphenoxy)-N-(4-methyl-thiazol-2-yl)-5-(piperidin-4-yl-oxy)-benzamidehydrochloride,5-(1-acetyl-piperidin-4-yloxy)-3-(4-methanesulfonylphenoxy)-N-(4-methyl-thiazol-2-yl)-benzamide,2-[3-(4-methanesulfonylphenoxy)-5-(4-methyl-thiazol-2-yl-carbamoyl)-phenoxy]propionicacid,5-(3-hydroxy-1-methyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,3-(4-methanesulfonylphenoxy)-5-(1-methylcarbamoyl-ethoxy)-N-(4-methyl-thiazol-2-yl)-benzamide,5-(2-acetylamino-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-5-isopropoxy-3-(4-methanesulfonylphenoxy)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-pyridin-2-yl-benzamide,5-(2-hydroxy-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-cyclopentyloxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,N-(4-acetyl-thiazol-2-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methanesulfonylphenoxy)-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-benzamide,3-(3-fluoro-4-methanesulfonylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(5-methyl-thiazol-2-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-([1,2,4]thiadiazol-5-yl)-benzamide,N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(5-methoxycarbonyl-pyridin-2-yl)-benzamide,6-[5-isopropoxy-3-(4-methanesulfonylphenoxy)-benzoylamino]nicotinicacid,5-(2-hydroxy-1-methyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)-3-(4-methanesulfonylphenoxy)-benzamide,N-(5-hydroxymethyl-thiazol-2-yl)-5-isopropoxy-3-(4-methanesulfonylphenoxy)-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-benzamide,N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methanesulfonylphenoxy)-5-(tetrahydrofuran-3-yl-oxy)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(2-methylthiazol-4-yl)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(4-methoxymethyl-thiazol-2-yl)-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-3-(4-methanesulfonylphenoxy)-5-(tetrahydrofuran-3-yl-oxy)-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-3-(4-methanesulfonylphenoxy)-5-(tetrahydrofuran-3-yl-oxy)-benzamide,N-(2,5-dimethylthiazol-4-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-benzamide,5-isopropoxy-3-(4-methoxycarbonylaminomethylphenoxy)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(4-methylcarbamoyl-phenoxy)-N-thiazol-2-yl-benzamide,3-(4-dimethylcarbamoyl-phenoxy)-5-isopropoxy-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(4-methylcarbonylaminomethyl-phenoxy)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(4-methanesulfonylaminomethyl-phenoxy)-N-thiazol-2-yl-benzamide,3-[4-(1-hydroxy-propyl)-phenoxy]-5-isopropoxy-N-thiazol-2-yl-benzamide,6-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl)-phenoxy]-nicotinic acid methylester,3-(5-hydroxymethyl-pyridin-2-yl-oxy)-5-isopropoxy-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(5-methanesulfonylpyridin-2-yl)-N-thiazol-2-yl-benzamide,3-(5-acetyl-pyridin-2-yl-oxy)-5-isopropoxy-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(5-methoxycarbonyl-pyrazin-2-yl-oxy)-N-thiazol-2-yl-benzamide,3-(5-cyano-pyridin-2-yl-oxy)-5-isopropoxy-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridin-4-yl-oxy)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridin-3-yl-oxy)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridin-3-yl-oxy)-N-thiazolo[5,4-b]pyridin-2-yl-benzamide,5-isopropoxy-3-([1,3,4]thiadiazol-2-ylsulfanyl)-N-thiazolo[5,4-b]-pyridine-2-yl-benzamide,5-isopropoxy-3-(4-methyl-[1,2,4]triazol-3-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-thiazol-2-ylsulfanyl-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(4H-[1,2,4]triazol-3-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-([1,3,4]thiadiazol-2-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(5-methylsulfanyl-[1,3,4]thiadiazol-2-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-(tetrahydrofuran-3-yl-oxy)-N-thiazol-2-yl-3-(4H-[1,2,4]triazol-3-ylsulfanyl)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(4-methyl-thiazol-2-yl)-3-([1,3,4]thiadiazol-2-ylsulfanyl)-benzamide,5-(3-hydroxy-1-methyl-propoxy)-N-(4-methyl-thiazol-2-yl)-3-([1,3,4]thiadiazol-2-ylsulfanyl)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-([1,3,4]thiadiazol-2-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenylsulfanyl)-N-thiazol-2-yl-benzamide,3-(3-fluoro-phenylthio)-5-(2-hydroxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(pyridin-4-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methyl-pyridin-3-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(3-methyl-[1,2,4]-thiadiazol-5-yl)-benzamide,N-[3-hydroxymethyl-1,2,4-thiadiazol-5-yl]-3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)benzamide,5-(3-hydroxy-1-methylethoxy)-3-(4-methanesulfonylphenoxy)-N-[5-methyl-1,2,4-thiadiazol-3-yl]benzamide,5-(hydroxy-1-methylethoxy)-3-(4-methanesulfonylphenoxy)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(1,2,5-thiadiazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(4-trifluoromethyl-thiazol-2-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(4,5,6,7-tetrahydrobenzothiazol-2-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(pyridazin-3-yl)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(3-isopropyl-[1,2,4]-triazol-5-yl)-3-(4-methanesulfonylphenoxy)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(3-methyl-[1,2,4]-oxadiazol-5-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-thiazol-2-yl]-3-(4-methanesulfonylphenoxy)benzamide,N-(4-cyano-thiazol-2-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(1-hydroxymethyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-(pyridin-2-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(5-methyl-isothiazol-3-yl)benzamide,5-(3-hydroxy-cyclopentyloxy)-3-(4-methanesulfonylphenoxy)-N-(thiazol-2-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(5-methoxy-thiazol-2-yl)benzamide,5-(1-hydroxymethyl-2-methyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-(thiazol-2-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(1H-[1,2,3]triazol-4-yl)benzamide,N-(1-acetyl-1H-pyrazol-3-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(pyrazol-3-yl)benzamide,N-(5,6-dihydro-4H-cyclopentathiazol-2-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)benzamide,5-(1-hydroxymethyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(thieno[3,2-d]thiazol-2-yl)benzamide,3-(3-fluoro-4-methanesulfonylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-N-(pyrazol-3-yl)benzamide,3-(4-cyano-phenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(4-ethylsulfonylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(3-hydroxy-1-methyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(4-ethanesulfonylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-isopropylsulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(4-hydroxy-4-methyl-4,5,6,6a-tetrahydro-3aH-cyclopentathiazol-2-yl)-3-(4-methanesulfonylphenoxy)benzamide,3-(4-dimethylcarbamoyl-phenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(4-acetylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-3-(1,3,4-thiadiazol-2-ylsulfanyl)benzamide,N-(1-ethyl-1H-pyrazol-3-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methoxycarbonylaminomethyl-phenoxy)-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide,5-(1-hydroxymethyl-propoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-methanesulfonylpyridin-3-yloxy)-5-(1-methoxymethyl-propoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-isopropoxy-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenylsulfanyl)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-cyclopropyloxy-3-(4-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-methanesulfonylpyridin-3-yloxy)-5-(1-methoxymethyl-propoxy)-N-(pyrazol-3-yl)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(1-hydroxymethyl-propoxy)-N(1-methyl-1H-pyrazol-3-yl)benzamide,5-(6-ethanesulfonylpyridin-3-yloxy)-3-(2-methoxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,2-[3-(4-methanesulfonylphenoxy)-5-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-phenoxy]propionicacid-tert-butyl ester,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-methoxy-1-methyl-ethoxy)-N-(pyrazol-3-yl)-benzamide,3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)-5-(tetrahydrofuran-3-yl)benzamide,N-(1-ethyl-1H-pyrazol-3-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(pyrazol-3-yl)benzamide,3-(6-methanesulfonylpyridin-3-yloxy)-5-(2-methoxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-fluoro-1-fluoromethyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,2-[3-(4-methanesulfonylphenoxy)-5-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-phenoxy]propionicacid,3-(6-ethanesulfonylpyridin-3-yloxy)-5-isopropoxy-N-(pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-isopropoxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(pyridin-2-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide-5-(2-fluoro-1-methyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-chloro-1-methyl-ethoxy)-3-(6-ethanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-N-(isoxazol-3-yl)-3-(6-methanesulfonylpyridin-3-yloxy)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(pyridin-2-yl)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(3-methyl-[1,2,4]-thiadiazol-5-yl)benzamide,3-(4-dimethylsulfamoylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(3-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(6-isopropylsulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(3-chloro-4-methanesulfonylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-3-(pyridin-3-yloxy)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-3-(pyridin-3-yloxy)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-3-(pyridin-4-yloxy)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-3-(pyridin-4-yloxy)benzamide,2-[3-(6-ethanesulfonylpyridin-3-yloxy)-5-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-phenoxy]propionicacid and5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(3-fluoro-4-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,among which examples of preferred compounds include5-isopropoxy-3-(4-methanesulfonylphenoxy)-N-(4-methylthiazol-2-yl)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,5-ethoxy-3-(4-methanesulfonylphenoxy)-N-(4-methoxymethyl-thiazol-2-yl)benzamide,5-cyclopentyloxy-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,3-(4-methanesulfonylphenoxy)-5-(tetrahydrofuran-3-yloxy)-N-thiazol-2-yl-benzamide,3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide,3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methoxymethyl-ethoxy)-N-thiazol-2-yl-benzamide,3-(2-fluoro-4-methanesulfonylphenoxy)-5-isopropoxy-N-thiazol-2-yl-benzamide,3-(4-methanesulfonylphenoxy)-5-(1-methoxymethyl-propoxy)-N-(4-methyl-thiazol-2-yl)-benzamide,3-(4-methanesulfonylphenoxy)-5-(3-methoxy-1-methyl-propoxy)-N-thiazol-2-yl-benzamide,5-(3-hydroxy-1-methyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,N-(4-hydroxymethyl-thiazol-2-yl)-5-isopropoxy-3-(4-methanesulfonylphenoxy)-benzamide,N-(isooxazol-3-yl)-3-(4-methanesulfonylphenoxy)-5-(1-methoxymethyl-propoxy)-benzamide,3-(4-methanesulfonylphenoxy)-5-(1-methoxymethyl-propoxy)-N-[1,3,4]thiadiazol-2-yl-benzamide,5-(1-hydroxymethyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-(4-methyl-thiazol-2-yl)-benzamide,N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methanesulfonylphenoxy)-5-(1-methoxymethyl-propoxy)-benzamide,5-(2-amino-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-propoxy)-3-(4-methanesulfonylphenoxy)-N-(4-methyl-thiazol-2-yl)-benzamide,3-(4-methanesulfonylphenoxy)-5-(2-methoxy-propoxy)-N-(4-methyl-thiazol-2-yl)-benzamide,5-isopropoxy-3-(4-methanesulfonylphenoxy)-N-(thiazolo[5,4-b]pyridin-2-yl)-benzamide,5-(2-hydroxymethyl-allyl)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazolo[5,4-b]pyridin-2-yl-benzamide,5-(3-hydroxy-2-methyl-propyl)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,5-(1-acetyl-piperidin-4-yloxy)-3-(4-methanesulfonylphenoxy)-N-(4-methyl-thiazol-2-yl)-benzamide,2-[3-(4-methanesulfonylphenoxy)-5-(4-methyl-thiazol-2-yl-carbamoyl)-phenoxy]propionicacid,5-(3-hydroxy-1-methyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,5-(2-acetylamino-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-5-isopropoxy-3-(4-methanesulfonylphenoxy)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-pyridin-2-yl-benzamide,5-(2-hydroxy-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-cyclopentyloxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,N-(4-acetyl-thiazol-2-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methanesulfonylphenoxy)-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-benzamide,3-(3-fluoro-4-methanesulfonylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(5-methyl-thiazol-2-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-([1,2,4]thiadiazol-5-yl)-benzamide,N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(5-methoxycarbonyl-pyridin-2-yl)-benzamide,6-[5-isopropoxy-3-(4-methanesulfonylphenoxy)-benzoylamino]nicotinicacid,5-(2-hydroxy-1-methyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)-3-(4-methanesulfonylphenoxy)-benzamide,N-(5-hydroxymethyl-thiazol-2-yl)-5-isopropoxy-3-(4-methanesulfonylphenoxy)-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-benzamide,N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methanesulfonylphenoxy)-5-(tetrahydrofuran-3-yl-oxy)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(2-methylthiazol-4-yl)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(4-methoxymethyl-thiazol-2-yl)-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-3-(4-methanesulfonylphenoxy)-5-(tetrahydrofuran-3-yl-oxy)-benzamide,N-[4-(1-hydroxyethyl)-thiazol-2-yl]-3-(4-methanesulfonylphenoxy)-5-(tetrahydrofuran-3-yl-oxy)-benzamide,N-(2,5-dimethylthiazol-4-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-benzamide,5-isopropoxy-3-(4-methoxycarbonylaminomethylphenoxy)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(4-methylcarbamoyl-phenoxy)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(4-methylcarbonylaminomethyl-phenoxy)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(4-methanesulfonylaminomethyl-phenoxy)-N-thiazol-2-yl-benzamide,3-[4-(1-hydroxy-propyl)-phenoxy]-5-isopropoxy-N-thiazol-2-yl-benzamide,6-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl)-phenoxy]-nicotinic acid methylester,3-(5-hydroxymethyl-pyridin-2-yl-oxy)-5-isopropoxy-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(5-methanesulfonylpyridin-2-yl)-N-thiazol-2-yl-benzamide,3-(5-acetyl-pyridin-2-yl-oxy)-5-isopropoxy-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(5-methoxycarbonyl-pyrazin-2-yl-oxy)-N-thiazol-2-yl-benzamide,3-(5-cyano-pyridin-2-yl-oxy)-5-isopropoxy-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridin-4-yl-oxy)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridin-3-yl-oxy)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridin-3-yl-oxy)-N-thiazolo[5,4-b]pyridin-2-yl-benzamide,5-isopropoxy-3-([1,3,4]thiadiazol-2-ylsulfanyl)-N-thiazolo[5,4-b]-pyridin-2-yl-benzamide,5-isopropoxy-3-(4-methyl-[1,2,4]triazol-3-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-thiazol-2-ylsulfanyl-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(4H-[1,2,4]triazol-3-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-([1,3,4]thiadiazol-2-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(5-methylsulfanyl-[1,3,4]thiadiazol-2-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-(tetrahydrofuran-3-yl-oxy)-N-thiazol-2-yl-3-(4H-[1,2,4]triazol-3-ylsulfanyl)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(4-methyl-thiazol-2-yl)-3-([1,3,4]thiadiazol-2-ylsulfanyl)-benzamide,5-(3-hydroxy-1-methyl-propoxy)-N-(4-methyl-thiazol-2-yl)-3-([1,3,4]thiadiazol-2-ylsulfanyl)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-([1,3,4]thiadiazol-2-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenylsulfanyl)-N-thiazol-2-yl-benzamide,3-(3-fluoro-phenylthio)-5-(2-hydroxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(pyridin-4-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methyl-pyridin-3-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(3-methyl-[1,2,4]-thiadiazol-5-yl)-benzamide,N-[3-hydroxymethyl-1,2,4-thiadiazol-5-yl]-3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)benzamide,5-(hydroxy-1-methylethoxy)-3-(4-methanesulfonylphenoxy)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(1,2,5-thiadiazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(3-isopropyl-[1,2,4]-triazol-5-yl)-3-(4-methanesulfonylphenoxy)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-thiazol-2-yl]-3-(4-methanesulfonylphenoxy)benzamide,N-(4-cyano-thiazol-2-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(1-hydroxymethyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-(pyridin-2-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(5-methyl-isothiazol-3-yl)benzamide,5-(3-hydroxy-cyclopentyloxy)-3-(4-methanesulfonylphenoxy)-N-(thiazol-2-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(5-methoxy-thiazol-2-yl)benzamide,5-(1-hydroxymethyl-2-methyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-(thiazol-2-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(1H-[1,2,3]triazol-4-yl)benzamide,N-(1-acetyl-1H-pyrazol-3-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(pyrazol-3-yl)benzamide,N-(5,6-dihydro-4H-cyclopentathiazol-2-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)benzamide,5-(1-hydroxymethyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(thieno[3,2-d]thiazol-2-yl)benzamide,3-(3-fluoro-4-methanesulfonylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-N-(pyrazol-3-yl)benzamide,3-(4-cyano-phenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(4-ethylsulfonylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(3-hydroxy-1-methyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(4-ethanesulfonylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-isopropylsulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(4-hydroxy-4-methyl-4,5,6,6a-tetrahydro-3aH-cyclopentathiazol-2-yl)-3-(4-methanesulfonylphenoxy)benzamide,3-(4-acetylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,N-(1-ethyl-1H-pyrazol-3-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methoxycarbonylaminomethyl-phenoxy)-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide,5-(1-hydroxymethyl-propoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-methanesulfonylpyridin-3-yloxy)-5-(1-methoxymethyl-propoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-isopropoxy-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)benzamide,3-(6-methanesulfonylpyridin-3-yloxy)-5-(1-methoxymethyl-propoxy)-N-(pyrazol-3-yl)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(1-hydroxymethyl-propoxy)-N(1-methyl-1H-pyrazol-3-yl)benzamide,5-(6-ethanesulfonylpyridin-3-yloxy)-3-(2-methoxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-methoxy-1-methyl-ethoxy)-N-(pyrazol-3-yl)-benzamide,3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)-5-(tetrahydrofuran-3-yl)benzamide,N-(1-ethyl-1H-pyrazol-3-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(pyrazol-3-yl)benzamide,3-(6-methanesulfonylpyridin-3-yloxy)-5-(2-methoxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-fluoro-1-fluoromethyl-ethoxy)-N-1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-isopropoxy-N-(pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-isopropoxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(pyridin-2-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide5-(2-fluoro-1-methyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-chloro-1-methyl-ethoxy)-3-(6-ethanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-N-(isoxazol-3-yl)-3-(6-methanesulfonylpyridin-3-yloxy)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(pyridin-2-yl)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(3-methyl-[1,2,4]-thiadiazol-5-yl)benzamide,3-(4-dimethylsulfamoylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(3chloro-4-methanesulfonylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-3-(pyridin-3-yloxy)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-3-(pyridin-3-yloxy)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-3-(pyridin-4-yloxy)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-3-(pyridin-4-yloxy)benzamideand5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(3-fluoro-4-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,examples of more preferred compounds include5-isopropoxy-3-(4-methanesulfonylphenoxy)-N-(4-methylthiazol-2-yl)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,3-(4-methanesulfonylphenoxy)-5-(tetrahydrofuran-3-yloxy)-N-thiazol-2-yl-benzamide,3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide,3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methoxymethyl-ethoxy)-N-thiazol-2-yl-benzamide,3-(2-fluoro-4-methanesulfonylphenoxy)-5-isopropoxy-N-thiazol-2-yl-benzamide,3-(4-methanesulfonylphenoxy)-5-(1-methoxymethyl-propoxy)-N-(4-methyl-thiazol-2-yl)-benzamide,3-(4-methanesulfonylphenoxy)-5-(3-methoxy-1-methyl-propoxy)-N-thiazol-2-yl-benzamide,N-(4-hydroxymethyl-thiazol-2-yl)-5-isopropoxy-3-(4-methanesulfonylphenoxy)-benzamide,N-(isooxazol-3-yl)-3-(4-methanesulfonylphenoxy)-5-(1-methoxymethyl-propoxy)-benzamide,3-(4-methanesulfonylphenoxy)-5-(1-methoxymethyl-propoxy)-N-[1,3,4]thiadiazol-2-yl-benzamide,5-(1-hydroxymethyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-(4-methyl-thiazol-2-yl)-benzamide,N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methanesulfonylphenoxy)-5-(1-methoxymethyl-propoxy)-benzamide,5-isopropoxy-3-(4-methanesulfonylphenoxy)-N-(thiazolo[5,4-b]pyridin-2-yl)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazolo[5,4-b]pyridin-2-yl-benzamide,5-(3-hydroxy-2-methyl-propyl)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,5-(3-hydroxy-1-methyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,5-(2-acetylamino-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-5-isopropoxy-3-(4-methanesulfonylphenoxy)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-pyridin-2-yl-benzamide,5-(2-hydroxy-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-cyclopentyloxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,N-(4-acetyl-thiazol-2-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methanesulfonylphenoxy)-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-benzamide,3-(3-fluoro-4-methanesulfonylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-([1,2,4]thiadiazol-5-yl)-benzamide,N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-benzamide,6-[5-isopropoxy-3-(4-methanesulfonylphenoxy)-benzoylamino]nicotinicacid,5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)-3-(4-methanesulfonylphenoxy)-benzamide,N-(5-hydroxymethyl-thiazol-2-yl)-5-isopropoxy-3-(4-methanesulfonylphenoxy)-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-benzamide,N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methanesulfonylphenoxy)-5-(tetrahydrofuran-3-yl-oxy)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(2-methylthiazol-4-yl)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(4-methoxymethyl-thiazol-2-yl)-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-3-(4-methanesulfonylphenoxy)-5-(tetrahydrofuran-3-yl-oxy)-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-3-(4-methanesulfonylphenoxy)-5-(tetrahydrofuran-3-yl-oxy)-benzamide,N-(2,5-dimethylthiazol-4-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-benzamide,3-(5-acetyl-pyridin-2-yl-oxy)-5-isopropoxy-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridin-4-yl-oxy)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridin-3-yl-oxy)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridin-3-yl-oxy)-N-thiazolo[5,4-b]pyridin-2-yl-benzamide,5-isopropoxy-3-([1,3,4]thiadiazol-2-ylsulfanyl)-N-thiazolo[5,4-b]-pyridine-2-yl-benzamide,5-isopropoxy-3-thiazol-2-ylsulfanyl-N-thiazol-2-yl-benzamide,5-isopropoxy-3-([1,3,4]thiadiazol-2-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(4-methyl-thiazol-2-yl)-3-([1,3,4]thiadiazol-2-ylsulfanyl)-benzamide,5-(3-hydroxy-1-methyl-propoxy)-N-(4-methyl-thiazol-2-yl)-3-([1,3,4]thiadiazol-2-ylsulfanyl)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-([1,3,4]thiadiazol-2-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenylsulfanyl)-N-thiazol-2-yl-benzamide,3-(3-fluoro-phenylthio)-5-(2-hydroxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(pyridin-4-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methyl-pyridin-3-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(3-methyl-[1,2,4]-thiadiazol-5-yl)-benzamide,5-(hydroxy-1-methylethoxy)-3-(4-methanesulfonylphenoxy)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(3-isopropyl-[1,2,4]-triazol-5-yl-3-(4-methanesulfonylphenoxy)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-thiazol-2-yl]-3-(4-methanesulfonylphenoxy)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(1-hydroxymethyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-(pyridin-2-yl)benzamide,5-(1-hydroxymethyl-2-methyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-(thiazol-2-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(pyrazol-3-yl)benzamide,N-(5,6-dihydro-4H-cyclopentathiazol-2-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)benzamide,5-(1-hydroxymethyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(3-fluoro-4-methanesulfonylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-N-(pyrazol-3-yl)benzamide,3-(4-ethylsulfonylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(4-ethanesulfonylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-isopropylsulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(4-hydroxy-4-methyl-4,5,6,6a-tetrahydro-3aH-cyclopentathiazol-2-yl)-3-(4-methanesulfonylphenoxy)benzamide,3-(4-acetylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methoxycarbonylaminomethyl-phenoxy)-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide,5-(1-hydroxymethyl-propoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-methanesulfonylpyridin-3-yloxy)-5-(1-methoxymethyl-propoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-isopropoxy-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)benzamide,3-(6-methanesulfonylpyridin-3-yloxy)-5-(1-methoxymethyl-propoxy)-N-(pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(1-hydroxymethyl-propoxy)-N(1-methyl-1H-pyrazol-3-yl)benzamide,5-(6-ethanesulfonylpyridin-3-yloxy)-3-(2-methoxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-methoxy-1-methyl-ethoxy)-N-(pyrazol-3-yl)-benzamide,N-(1-ethyl-1H-pyrazol-3-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(pyrazol-3-yl)benzamide,3-(6-methanesulfonylpyridin-3-yloxy)-5-(2-methoxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-isopropoxy-N-(pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-isopropoxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide5-(2-fluoro-1-methyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(3-methyl-[1,2,4]-thiadiazol-5-yl)benzamide,3-(4-dimethylsulfamoylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamideand3-(3-chloro-4-methanesulfonylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,and examples of particularly preferred compounds include5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,3-(4-methanesulfonylphenoxy)-5-(tetrahydrofuran-3-yloxy)-N-thiazol-2-yl-benzamide,3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide,3-(4-methanesulfonylphenoxy)-5-(1-methoxymethyl-propoxy)-N-(4-methyl-thiazol-2-yl)-benzamide,N-(4-hydroxymethyl-thiazol-2-yl)-5-isopropoxy-3-(4-methanesulfonylphenoxy)-benzamide,N-(isooxazol-3-yl)-3-(4-methanesulfonylphenoxy)-5-(1-methoxymethyl-propoxy)-benzamide,3-(4-methanesulfonylphenoxy)-5-(1-methoxymethyl-propoxy)-N-[1,3,4]thiadiazol-2-yl-benzamide,5-(1-hydroxymethyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-(4-methyl-thiazol-2-yl)-benzamide,N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methanesulfonylphenoxy)-5-(1-methoxymethyl-propoxy)-benzamide,5-isopropoxy-3-(4-methanesulfonylphenoxy)-N-(thiazolo[5,4-b]pyridin-2-yl)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazolo[5,4-b]pyridin-2-yl-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-5-isopropoxy-3-(4-methanesulfonylphenoxy)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-pyridin-2-yl-benzamide,5-(2-hydroxy-cyclopentyloxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methanesulfonylphenoxy)-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-([1,2,4]thiadiazol-5-yl)-benzamide,N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-benzamide,N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methanesulfonylphenoxy)-5-(tetrahydrofuran-3-yl-oxy)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(2-methylthiazol-4-yl)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(4-methoxymethyl-thiazol-2-yl)-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-3-(4-methanesulfonylphenoxy)-5-(tetrahydrofuran-3-yl-oxy)-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-3-(4-methanesulfonylphenoxy)-5-(tetrahydrofuran-3-yl-oxy)-benzamide,N-(2,5-dimethylthiazol-4-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-benzamide,5-isopropoxy-3-([1,3,4]thiadiazol-2-ylsulfanyl)-N-thiazolo[5,4-b]-pyridine-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-([1,3,4]thiadiazol-2-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(3-methyl-[1,2,4]-thiadiazol-5-yl)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(1-hydroxymethyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(3-fluoro-4-methanesulfonylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy-N-isoxazol-3-yl)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-isopropoxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide.

The heteroarylcarbamoylbenzene derivatives of the present invention mayalso be used as pharmaceutically acceptable salts. Such salts may beacid addition salts or base addition salts.

Depending on the manner of the substituents, the compounds of theinvention may also exist as stereoisomers or tautomers, includingoptical isomers, diastereomers and geometric isomers. All such isomersare, needless to mention, included in the compounds of the invention.Any desired mixtures of such isomers are also, needless to mention,included in the compounds of the invention.

Since the compounds of the invention have glucokinase-activatingeffects, they are useful as therapeutic and/or prophylactic agents fordiabetes, and also as therapeutic and/or prophylactic agents fordiabetes complications.

Here, “diabetes complications” refers to conditions which occur inassociation with diabetes, and examples of such diabetes complicationsinclude diabetic nephropathy, diabetic retinopathy, diabetic neuropathyand diabetic arteriosclerosis.

The compounds of the invention may be applied for eitherinsulin-dependent diabetes mellitus (IDDM) or non-insulin-dependentdiabetes mellitus (NIDDM).

Insulin-dependent diabetes mellitus (IDDM) is considered to be caused byreduction in insulin secretion and insulin resistance in the skeletalmuscle due to genetic factors, while non-insulin-dependent diabetesmellitus (NIDDM) is considered to be predominantly an adult onset form,with increasing insulin resistance associated with obesity. Diabetes istherefore classified as type I (IDDM) or type II (NIDDM), depending onthe cause.

The compounds of the invention are believed to be useful not only fortype I diabetes, but also for type II diabetes for which adequate bloodglucose level reduction has not been possible using conventionaldiabetes drugs.

In type II diabetes, the degree of postprandial hyperglycemia continuesfor a notably more prolonged period than in healthy persons, and thecompounds of the invention are also useful against this type IIdiabetes.

Preferred Mode of the Invention

Processes for production of compounds of the invention will now beexplained.

Compound (I) of the present invention may be easily produced usingpublicly known reaction means, or by carrying out a publicly knownmethod. A compound (I) of the present invention may also be produced bya synthesis method in an ordinary liquid phase, as well as by a methodemploying a solid phase such as, for example, combinatorial synthesis orparallel synthesis methods, which have undergone rapid development inrecent years.

The compounds of the invention are preferably produced by the followingscheme, for example.

[wherein R represents lower alkyl, X represents a halogen atom, and theother symbols have the same definitions specified above].

(Step 1-1) This step introduces a protective group at the carboxyl groupof 3,5-dihydrobenzoic acid (1a) to produce compound (1).

The protective group R for the carboxyl group of compound (1) functionsas a protective group for the carboxyl group through Steps 1 to 3 and itmay be any group so long as it can be easily removed in Step 4. Asexamples there may be mentioned straight-chain or branched lower alkylgroups such as methyl, ethyl and tert-butyl, halogenated lower alkylgroups such as 2-ethyl iodide and 2,2,2-trichloroethyl, lower alkenylgroups such as allyl, 2-propenyl and 2-methyl-2-propenyl, or aralkylgroups such as benzyl and PMB.

The method of introducing and removing the protective group R for thecarboxyl group may be a method described in the relevant literature (forexample, Protective Groups in Organic Synthesis, T. W. Green, 2ndprinting, John Wiley & Sons, 1991), a corresponding method, or acombination thereof with an ordinary method.

Compound (1) obtained in this manner may be isolated and purified bypublicly known separation and purification means such as, for example,concentration, concentration under reduced pressure, solvent extraction,crystallization, reprecipitation or chromatography, or it may besupplied to the subsequent step without isolation and purification.

(Step 1) In this step, compound (1) and p-methylthiophenylboric acid (2)are reacted in the presence of copper acetate and a base to produce a5-hydroxy-3-(4-methylthiophenoxy)benzoic acid ester (3).

The amount of p-methylthiophenylboric acid (2) used will usually be from1 to 10 equivalents, and preferably from 1 to 2.5 equivalents, withrespect to 1 equivalent of compound (1).

Copper nitrate may be used instead of copper acetate, but copper acetateis preferred.

The amount of copper acetate or copper nitrate used will usually be from0.1 to 5 equivalents, and preferably from 1 to 1.5 equivalents.

As examples of bases to be used there may be mentioned triethylamine,diisopropylethylamine, and the like, among which triethylamine ispreferred.

The amount of base used will usually be from 0 to 10 equivalents, andpreferably from 4 to 6 equivalents.

The reaction temperature will usually be from 0° C. to the refluxtemperature of the reaction solvent, and preferably from 15 to 30° C.

The reaction time in this step will usually be from 2 to 48 hours, andpreferably 12 hours.

The reaction solvent used in this step may be any one which does notimpede the reaction, and as examples there may be mentioned methylenechloride, acetonitrile, toluene and the like, among which methylenechloride is preferred.

Compound (3) obtained in this manner may be isolated and purified bypublicly known separation and purification means such as, for example,concentration, concentration under reduced pressure, crystallization,solvent extraction, reprecipitation or chromatography, or it may besupplied to the subsequent step without isolation and purification.

(Step 2) In this step, compound (3) obtained in Step 1 above and analkyl halide (4) are reacted in the presence of a base to producecompound (5).

As compound (4) there may be used any compound which allows the reactionof this step to proceed uninhibited to produce compound (5), and asexamples there may be mentioned ethyl iodide, 2-propyl bromide,cyclopentyl bromide, 2-bromoethanol and the like, among which 2-propylbromide and cyclopentyl bromide, for example, are preferred, and2-propyl bromide is more preferred.

The amount of compound (4) used will usually be from 0.5 to 10equivalents, and preferably from 1 to 3 equivalents, with respect to 1equivalent of compound (3).

As examples of bases to be used there may be mentioned potassiumcarbonate, diisopropylamine and the like, among which potassiumcarbonate is preferred.

The amount of the base used will usually be from 1 to 10 equivalents,and preferably from 1.5 to 3 equivalents.

The reaction temperature will usually be from 0° C. to the refluxtemperature of the reaction solvent, and preferably from 25 to 40° C.

The reaction time will usually be from 1 to 12 hours, and preferablyfrom 4 to 8 hours.

The reaction solvent used in this step may be any one which does notimpede the reaction, but N,N-dimethylformamide is preferred.

Compound (5) obtained in this manner may be isolated and purified bypublicly known separation and purification means such as, for example,concentration, concentration under reduced pressure, solvent extraction,crystallization, reprecipitation or chromatography, or it may besupplied to the subsequent step without isolation and purification.

(Step 3) In this step, compound (5) obtained in Step 2 above is reactedwith mCPBA to produce compound (6). The oxidation reaction conducted inthis step may be according to a method described in the relevantliterature (for example, Brown. D. et al., Simple pyrimidines. X. Theformation and reactivity of 2-, 4-, and 5-pyrimidinyl sulfones andsulfoxides, Journal of the Chemical Society [Section]C: Organic, Vol. 7,1967, p568-572), a corresponding method, or a combination thereof withan ordinary method.

The amount of mCPBA used will usually be from 2 to 10 equivalents, andpreferably from 3 to 4 equivalents, with respect to 1 equivalent ofcompound (5).

The reaction time will usually be from 10 minutes to 12 hours, andpreferably from 30 minutes to 1 hour.

The reaction temperature will usually be from −78 to 15° C., andpreferably from 0 to 10° C.

The reaction solvent used may be any one which does not impede thereaction, and as examples there may be mentioned methylene chloride,chloroform and the like, among which chloroform is preferred.

Compound (6) obtained in this manner may be isolated and purified bypublicly known separation and purification means such as, for example,concentration, concentration under reduced pressure, crystallization,reprecipitation, solvent extraction or chromatography, or it may besupplied to the subsequent step without isolation and purification.

(Step 4) In this step, the protective group R for the carboxyl group ofcompound (6) obtained in Step 3 above is removed to produce compound(7).

The method of removing the carboxyl protective group R may be a methoddescribed in the relevant literature (for example, Protective Groups inOrganic Synthesis, T. W. Green, 2nd printing, John Wiley & Sons, 1991),a corresponding method, or a combination thereof with an ordinarymethod.

Compound (7) obtained in this manner may be isolated and purified bypublicly known separation and purification means such as, for example,concentration, concentration under reduced pressure, solvent extraction,crystallization, reprecipitation or chromatography, or it may besupplied to the subsequent step without isolation and purification.

(Step 5) In this step, compound (7) obtained in Step 4 above is reactedwith an amino compound represented by the following formula (8):

[wherein the symbols have the same definitions specified above] toproduce compound (I-1).

This reaction may be accomplished by conducting an ordinaryamide-forming reaction by a method described in the relevant literature(for example, Peptide Gosei no Kiso to Jikken, Izumiya, N. et al.,Maruzen Publ., 1983, Comprehensive Organic Synthesis, Vol. 6, PergamonPress, 1991), a corresponding method, or a combination thereof with anordinary method, using, specifically, a condensation agent which is wellknown to those skilled in the art, or it may be carried out by anester-activating method, mixed acid anhydride method, acid chloridemethod, carbodiimide method, etc. available to those skilled in the art.As examples of such amide-forming reagents there may be mentionedthionyl chloride, oxalyl chloride, N,N-dicyclohexylcarbodiimide,1-methyl-2-bromopyridinium iodide, N,N′-carbonyldiimidazole,diphenylphosphoryl chloride, diphenylphosphorylazide,N,N′-disuccinimidyl carbonate, N,N′-disuccinimidyl oxalate,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, ethylchloroformate, isobutyl chloroformate,benzotriazo-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphateand the like, among which thionyl chloride,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride,N,N-dicyclohexylcarbodiimide andbenzotriazo-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate,for example, are preferred. For an amide-forming reaction, a base andcondensation aid may be used together with the aforementionedamide-forming reagent.

As examples of bases to be used there may be mentioned tertiaryaliphatic amines such as trimethylamine, triethylamine,N,N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine,N-methylpiperidine, N,N-dimethylaniline,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and1,5-azabicyclo[4.3.0]non-5-ene (DBN) and aromatic amines such aspyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline andisoquinoline, among which tertiary aliphatic amines, for example, arepreferred, and triethylamine and N,N-diisopropylethylamine, for example,are particularly preferred.

As examples of condensation aids to be used there may be mentionedN-hydroxybenzotriazole hydrate, N-hydroxysuccinimide,N-hydroxy-5-norbomane-2,3-dicarboxyimide and3-hydroxy-3,4dihydro-4-oxo-1,2,3-benzotriazole, among whichN-hydroxybenzotriazole, for example, is preferred.

The amount of compound (8) used will differ depending on the types ofcompounds and solvent used and the other reaction conditions, but willusually be from 0.1 to 10 equivalents, and preferably from 0.5 to 3equivalents, with respect to 1 equivalent of the carboxylic acidderivative (7) or its reactive derivative.

The amount of amide-forming reagent used will differ depending on thetypes of compounds and solvent used and the other reaction conditions,but will usually be from 1 to 10 equivalents, and preferably from 1 to 3equivalents with respect to 1 equivalent of the carboxylic acid compound(7) or its reactive derivative.

The amount of condensation agent used will also differ depending on thetypes of compounds and solvent used and the other reaction conditions,but will usually be from 1 to 10 equivalents, and preferably from 1 to 3equivalents, with respect to 1 equivalent of the carboxylic acidcompound (7) or its reactive derivative.

The amount of base used will also differ depending on the types ofcompounds and solvent used and the other reaction conditions, but willusually be from 1 to 10 equivalents, and preferably from 1 to 5equivalents.

The reaction solvent used for this step may be, for example, an inertsolvent, and is not particularly restricted so long as it does notimpede the reaction, but as specific examples there may be mentionedmethylene chloride, chloroform, 1,2-dichloroethane,N,N-dimethylformamide, acetic acid ethyl ester, acetic acid methylester, acetonitrile, benzene, xylene, toluene, 1,4-dioxane,tetrahydrofuran, dimethoxyethane or mixtures thereof, among whichmethylene chloride, chloroform, 1,2-dichloroethane, acetonitrile,N,N-dimethylformamide and the like are preferred from the standpoint ofensuring a suitable reaction temperature.

The reaction temperature in this step will usually be from −78° C. tothe boiling point of the solvent, and preferably from 0 to 30° C.

The reaction time in this step will usually be from 0.5 to 96 hours, andpreferably from 3 to 24 hours.

The base, amide-forming reagent and condensation agent used for thisstep may each be a single type or a combination of more than one type.

When substituent R³ on Ring B of compound (I-1) produced in this stephas a protective group, the protective group may be removed ifnecessary. The removal of the protective group may be accomplished by amethod described in the relevant literature (for example, ProtectiveGroups in Organic Synthesis, T. W. Green, 2nd printing, John Wiley &Sons, 1991), a corresponding method, or a combination thereof with anordinary method.

Compound (I-1) of the present invention obtained in this manner may beisolated and purified by publicly known separation and purificationmeans such as, for example, concentration, concentration under reducedpressure, crystallization, solvent extraction, reprecipitation orchromatography.

Compound (5) produced in Step 3 above may also be produced by thefollowing method.

[wherein the symbols have the same definitions specified above]

(Step 6) In this step, compound (3) produced in Step 1 above is reactedwith an alcohol compound (9) to produce compound (5).

This reaction is a Mitsunobu reaction, which may be carried out in thepresence of a phosphine compound and an azo compound, according to amethod described in the relevant literature (for example, Mitsunobu, O.,The use of diethyl azodicarboxylate and triphenylphosphine in synthesisand transformation of natural products, Synthesis, Vol. 1, 1981, p1-28),a corresponding method, or a combination thereof with an ordinarymethod.

The amount of the alcohol compound (9) used in this step will usually befrom 0.5 to 10 equivalents, and preferably from 1 to 3 equivalents, withrespect to 1 equivalent of compound (3).

As ordinary examples of phosphine compounds to be used in this stepthere may be mentioned triphenylphosphine and triethylphosphine.

The amount of the phosphine compound used will usually be from 0.5 to 10equivalents, and preferably from 1 to 3 equivalents, with respect to 1equivalent of compound (3).

As examples of azo compounds to be used there may be mentioned diethylazodicarboxylate and diisopropyl azodicarboxylate.

The amount of the azo compound used will usually be from 0.5 to 10equivalents, and preferably from 1 to 3 equivalents with respect to 1equivalent of compound (3).

The reaction time in this step will usually be from 1 to 48 hours, andpreferably from 4 to 12 hours.

The reaction temperature in this step will usually be from 0° C. to thereflux temperature of the reaction solvent, and preferably from 15 to30° C.

The reaction solvent used in this step is not particularly restricted solong as it does not impede the reaction, and as specific examples theremay be mentioned tetrahydrofuran and toluene.

Compound (I-1) obtained in this manner may be isolated and purified bypublicly known separation and purification means such as, for example,concentration, concentration under reduced pressure, reprecipitation,solvent extraction, crystallization or chromatography, or it may besupplied to the subsequent step without isolation and purification.

Compound (I-2) of the present invention may be produced by the followingscheme.

[wherein the symbols have the same definitions specified above]

(Step 7) In this step, compound (1) obtained in the previous step isreacted with compound (4) to produce compound (10).

This step may be carried out by the same method as in Step 2 above.

The number of equivalents of the alkyl halide compound (4) with respectto compound (1), and the reaction conditions such as the reactiontemperature, reaction time, etc. may be according to the method of Step2 above, a corresponding method, or a combination thereof with anordinary method.

(Step 8) In this step, compound (10) obtained in Step 7 above is reactedwith a boric acid derivative represented by the following formula (11):

[wherein the symbols have the same definitions specified above] toproduce compound (12).

When R¹ requires a protective group, the necessary protective group maybe introduced according to the type of R¹ group. The protecting groupfor R¹ may be any group which functions as a protective group for R¹from Step 8 to Step 10 and which can be easily removed thereafter toyield compound (I-2) of the present invention.

The method of introducing and removing the protective group for R¹ maybe a method described in the relevant literature (for example,Protective Groups in Organic Synthesis, T. W. Green, 2nd printing, JohnWiley & Sons, 1991), a corresponding method, or a combination thereofwith an ordinary method.

Substituent R¹¹ on Ring A may be converted to R¹.

The conversion from substituent R¹¹ on Ring A to R¹ may be carried outby a method described in the relevant literature (for example,Comprehensive Organic Synthesis, Vol. 6, Pergamon Press, 1991;Comprehensive Organic Transformations, Richard L. et al., VCHPublishers, 1988), a corresponding method, or a combination thereof withan ordinary method.

As examples of groups for R¹¹ there may be mentioned formyl, halogenatoms and alkoxycarbonyl.

When R¹¹ is a formyl group, for example, the formyl group may be reducedto convert it to hydroxymethyl. The reaction for conversion of formyl tohydroxymethyl may be a reaction whereby a compound having a formyl groupis reacted with sodium borohydride to produce a compound havinghydroxymethyl as R¹.

Alternatively, a compound having hydroxymethyl as R¹ may be subjected toazidation followed by reduction reaction for conversion to aminomethyl.

Conversion reaction from an alkoxycarbonyl group to an alkylcarbamoylgroup may also be accomplished by hydrolyzing a compound having analkoxycarbonyl group and then subjecting it to an amide-forming reactionwith an alkylamine to produce a compound having an alkylcarbamoyl groupas R¹.

As examples of boric acid derivatives represented by formula (11) abovethere may be mentioned 4-bromo-phenylboric acid, 4-fluoro-phenylboricacid, 4-methyl-phenylboric acid, 4-methoxy-phenylboric acid,4-trifluoromethyl-phenylboric acid, 4-hydroxymethyl-phenylboric acid,4-acetyl-phenylboric acid, 4-cyano-phenylboric acid,4-methoxycarbonyl-phenylboric acid, 4-carboxy-phenylboric acid,4-formyl-phenylboric acid, 4-aminomethyl-phenylboric acid and4-carbamoyl-phenylboric acid.

When the phenylboric acid derivative represented by formula (11) has R¹¹as a substituent on Ring A, R¹¹ may have a protective group.

The method of introducing the protective group may be a method describedin the relevant literature (for example, Protective Groups in OrganicSynthesis, T. W. Green, 2nd printing, John Wiley & Sons, 1991), acorresponding method, or a combination thereof with an ordinary method.

The compound obtained in this manner may be isolated and purified bypublicly known separation and purification means such as, for example,concentration, concentration under reduced pressure, solvent extraction,crystallization, reprecipitation or chromatography, or it may besupplied to the subsequent step without isolation and purification.

(Step 9) In this step, the protective group R for the carboxyl group ofcompound (12) obtained in Step 8 above is removed. This step may becarried out under the same reaction conditions as in Step 4, by a methoddescribed in the relevant literature (for example, Protective Groups inOrganic Synthesis, T. W. Green, 2nd printing, John Wiley & Sons, 1991),a corresponding method, or a combination thereof with an ordinarymethod.

Compound (13) obtained in this manner may be isolated and purified bypublicly known separation and purification means such as, for example,concentration, concentration under reduced pressure, solvent extraction,crystallization, reprecipitation or chromatography, or it may besupplied to the subsequent step without isolation and purification.

(Step 10) In this step, compound (13) obtained in Step 9 above isreacted with an amino compound (8) to produce compound (I-2) of thepresent invention. This step may be carried out under the same reactionconditions as in Step 5.

Compound (I-2) of the present invention which is obtained in this mannermay be isolated and purified by publicly known separation andpurification means such as, for example, concentration, concentrationunder reduced pressure, solvent extraction, crystallization,reprecipitation or chromatography.

Compound (I-3) of the present invention may be produced by the followingscheme.

[wherein Y represents a halogen atom, and the other symbols have thesame definitions specified above]

(Step 11) In this step, compound (14) is reacted with compound (4) aboveto produce compound (14-1). The number of equivalents of compound (4)used with respect to 1 equivalent of the phenol derivative (14), and thereaction conditions such as the reaction temperature, reaction time,etc. in this step may be according to the method of Step 7 above.

Compound (14-1) obtained in this manner may be isolated and purified bypublicly known separation and purification means such as, for example,concentration, concentration under reduced pressure, solvent extraction,reprecipitation, crystallization or chromatography, or it may besupplied to the subsequent step without isolation and purification.

(Step 12) In this step, compound (14-1) obtained in Step 11 above isreacted with compound (15) to produce compound (16).

This reaction may be carried out by reacting compound (14-1) and amercapto derivative (15) in the presence of a base, hydroquinone andcopper bromide.

As bases to be used in this step there may be mentioned potassiumcarbonate, cesium carbonate, sodium hydride and the like, among whichpotassium carbonate and sodium hydride are preferred.

The amount of the base used in this step will usually be from 0.5 to 20equivalents, and preferably from 3 to 10 equivalents, with respect to 1equivalent of compound (14-1).

The amount of hydroquinone used in this step will usually be from 0.1 to10 equivalents, and preferably from 0.2 to 1.5 equivalents, with respectto 1 equivalent of compound (14-1).

The amount of copper bromide used in this step will usually be from 0.1to 10 equivalents, and preferably from 0.2 to 2 equivalents, withrespect to 1 equivalent of compound (14-1).

The reaction temperature will usually be from 25° C. to the refluxtemperature of the reaction solvent, and preferably from 50° C. to thereflux temperature of the reaction solvent.

The reaction time will usually be from 10 minutes to 24 hours, andpreferably from 15 minutes to 3 hours.

The reaction solvent used in this step is not particularly restricted solong as it does not impede the reaction, but a specific preferredexample is N,N-dimethylformamide.

Compound (16) obtained in this manner may be isolated and purified bypublicly known separation and purification means such as, for example,concentration, concentration under reduced pressure, solvent extraction,crystallization, reprecipitation or chromatography, or it may besupplied to the subsequent step without isolation and purification.

(Step 13) In this step, the protective group for the carboxyl group ofcompound (16) obtained in Step 12 above is removed to produce compound(17).

This step may be carried out according to the same method as in Step 4or 9, or by a method described in the relevant literature (for example,Protective Groups in Organic Synthesis, T. W. Green, 2nd printing, JohnWiley & Sons, 1991), a corresponding method, or a combination thereofwith an ordinary method.

Compound (17) obtained in this manner may be isolated and purified bypublicly known separation and purification means such as, for example,concentration, concentration under reduced pressure, solvent extraction,crystallization, reprecipitation or chromatography, or it may besupplied to the subsequent step without isolation and purification.

(Step 14) In this step, compound (17) obtained in Step 13 above isreacted with compound (8) to produce compound (I-3) of the presentinvention.

This reaction is an amide bond-forming reaction, and the reactionconditions including the reaction temperature and reaction solvent maybe the same as in Step 5 or Step 10 above.

Compound (I-3) of the present invention which is obtained in this mannermay be isolated and purified by publicly known separation andpurification means such as, for example, concentration, concentrationunder reduced pressure, solvent extraction, crystallization,reprecipitation or chromatography.

Compound (I-4) of the present invention may be produced according to thefollowing scheme.

[wherein the symbols have the same definitions specified above]

(Step 15) In this step, the protective group for the carboxyl group ofcompound (10) obtained in Step 7 above is removed. This step is carriedout under the same reaction conditions as in Step 4 above, or accordingto a method described in the relevant literature (for example,Protective Groups in Organic Synthesis, T. W. Green, 2nd printing, JohnWiley & Sons, 1991), a corresponding method, or a combination thereofwith an ordinary method.

Compound (18) obtained in this manner may be isolated and purified bypublicly known separation and purification means such as, for example,concentration, concentration under reduced pressure, solvent extraction,crystallization, reprecipitation or chromatography, or it may besupplied to the subsequent step without isolation and purification.

(Step 16) In this step, compound (18) obtained in Step 15 above isreacted with compound (8) to produce compound (19). This reaction is anamide bond-forming reaction, and the reaction conditions including thereaction temperature and reaction solvent may be the same as in Step 5or Step 10 above.

Compound (19) of the present invention which is obtained in this mannermay be isolated and purified by publicly known separation andpurification means such as, for example, concentration, concentrationunder reduced pressure, solvent extraction, crystallization,reprecipitation or chromatography, or it may be supplied to thesubsequent step without isolation and purification.

(Step 17) In this step, compound (19) obtained in Step 16 above isreacted with a halogen compound represented by the following formula(20):

[wherein Ring A represents a pyridine ring, pyrazine ring, pyrimidinering or pyridazine ring, and the other symbols have the same definitionsspecified above] in the presence of a base to produce compound (I-4) ofthe present invention.

The amount of the halogen compound (20) used in this step will usuallybe from 0.5 to 10 equivalents, and preferably from 1 to 3 equivalents,with respect to 1 equivalent of compound (19).

As bases to be used in this step there may be mentioned potassiumcarbonate, cesium carbonate, sodium hydride and the like, with potassiumcarbonate being preferred among these.

The amount of the base to be used in this step will usually be from 0.5to 20 equivalents, and preferably from 1 to 10 equivalents, with respectto 1 equivalent of compound (19).

The reaction temperature will generally be from 25° C. to the refluxtemperature of the reaction solvent, and it is preferably from 50° C. tothe reflux temperature of the reaction solvent.

The reaction time will usually be from 1 to 48 hours, and preferablyfrom 1 to 24 hours.

The reaction solvent used in this step is not particularly restricted solong as it does not impede the reaction, but a specific preferredexample is N,N-dimethylformamide.

When R¹ requires a protective group, the necessary protective group maybe introduced according to the type of R¹ group. The protecting groupfor R¹ may be any group which functions as a protective group for R¹ inStep 17 and which can be easily removed thereafter.

The method of introducing and removing the protective group for R¹ maybe a method described in the relevant literature (for example,Protective Groups in Organic Synthesis, T. W. Green, 2nd printing, JohnWiley & Sons, 1991), a corresponding method, or a combination thereofwith an ordinary method.

Substituent R¹¹ on Ring A may also be converted to R¹.

Conversion of substituent R¹¹ on Ring A to R¹ may be carried out by amethod described in the relevant literature (for example, ComprehensiveOrganic Synthesis, Vol. 6, Pergamon Press, 1991; Comprehensive OrganicTransformations, Richard L. et al., VCH Publishers, 1988), acorresponding method, or a combination thereof with an ordinary method.

As examples for R¹¹ there may be mentioned halogen atoms andalkoxycarbonyl.

When R¹¹ is, for example, alkoxycarbonyl, the alkoxycarbonyl may bereduced for conversion to hydroxymethyl.

The reaction for conversion of an alkoxycarbonyl to hydroxymethyl may bereaction between a compound having an alkoxycarbonyl group and lithiumaluminum hydride to produce a compound having hydroxymethyl as R¹.

Alternatively, a compound having hydroxymethyl as R¹ may be subjected toazidation followed by reduction reaction for conversion to aminomethyl.

When the halogen compound (20) represented by the formula shown abovehas R¹¹ as a substituent on Ring A, R¹¹ may also have a protectivegroup.

The method of introducing the protective group may be a method describedin the relevant literature (for example, Protective Groups in OrganicSynthesis, T. W. Green, 2nd printing, John Wiley & Sons, 1991), acorresponding method, or a combination thereof with an ordinary method.

Compound (I-4) obtained in this manner may be isolated and purified bypublicly known separation and purification means such as, for example,concentration, concentration under reduced pressure, solvent extraction,crystallization, reprecipitation or chromatography.

Compound (I-5) of the present invention may be produced by the followingscheme.

[wherein R²² represents R² optionally having a substituent, and theother symbols have the same definitions specified above]

(Step 18) In this step, compound (21) is reacted with a halogen compoundrepresented by formula (20) below:

[wherein R⁴ represents a protective group for hydroxy, and the othersymbols have the same definitions specified above] in the presence of abase, to produce compound (23).

The method of introducing the protective group R⁴ for the hydroxy groupof compound (21) used in this step may be a method described in theaforementioned literature (for example, Protective Groups in OrganicSynthesis, T. W. Green, 2nd printing, John Wiley & Sons, 1991), acorresponding method, or a combination thereof with an ordinary method.

This step may be carried out by the same method as in Step 17 above, acorresponding method, or a combination thereof with an ordinary method.

As examples of specific groups for R⁴ there may be mentionedmethoxymethyl, benzyl, 4-methoxy-benzyl, 2-(trimethylsilyl)ethoxymethyl,tert-butyldimethylsilyl and tert-butylcarbonyl.

The amount of compound (20) used will differ depending on the types ofcompounds and solvents used and the other reaction conditions, but itwill usually be from 0.1 to 20 equivalents, and preferably from 0.5 to 5equivalents, with respect to 1 equivalent of compound (21).

The amount of the base used will differ depending on the types ofcompounds and solvent used and the other reaction conditions, but itwill usually be from 0.1 to 20 equivalents, and preferably from 0.5 to 5equivalents.

The base used may be any one which allows compound (23) to be producedby reaction between compound (20) and compound (21) in this step, and asexamples there may be mentioned cesium carbonate, sodium carbonate,potassium carbonate, potassium phosphate, potassium acetate, potassiumtert-butyrate and triethylamine.

The reaction solvent used may be an inert solvent and it is notparticularly restricted so long as it does not impede the reaction, butas specific examples there may be mentioned pyridine, toluene,1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide,dimethylsulfoxide and 1-methyl-2-pyrrolidinone.

Copper (I) oxide, copper (II) oxide or copper (I) chloride may becopresent in the reaction system for this step.

Also, a palladium salt such as palladium (II) acetate or palladium (II)chloride and a ligand such as 2-(di-tert-butylphosphino)biphenyl ortriphenylphosphine may be copresent in the reaction system for thisstep.

In addition, silver carbonate, silver acetate, silver oxide, silvertrifluoroacetate or the like may also be copresent in the reactionsystem for this step.

The reaction temperature in this step will usually be from 0° C. to thereflux temperature of the reaction solvent, and preferably from roomtemperature to 150° C.

The reaction time in this step will usually be from 0.1 to 72 hours, andpreferably from 0.5 to 5 hours.

Compound (23) obtained in this manner may be isolated and purified bypublicly known separation and purification means such as, for example,concentration, concentration under reduced pressure, crystallization,solvent extraction, reprecipitation or chromatography, or it may besupplied to the subsequent step without isolation and purification.

(Step 19) In this step, the protective group for the hydroxy group ofcompound (23) obtained in Step 18 above is removed to produce compound(24).

The removal of the protective group in this step may be accomplished bya method described in the relevant literature (for example, ProtectiveGroups in Organic Synthesis, T. W. Green, 2nd printing, John Wiley &Sons, 1991), a corresponding method, or a combination thereof with anordinary method, or when R⁴ is methoxymethyl, removal of the protectivegroup may be accomplished using, for example, trifluoroacetic acid(TFA), hydrochloric acid or the like.

When TFA is used for removal of R⁴, the amount of TFA will usually befrom 0.5 to 1000 equivalents, and preferably from 1 to 100 equivalents.

When hydrochloric acid is used for removal of R⁴, the amount ofhydrochloric acid will usually be from 0.5 to 1000 equivalents, andpreferably from 1 to 100 equivalents.

The reaction solvent used in this step is not particularly restricted solong as it does not impede the reaction, and as examples there may bementioned methylene chloride, chloroform, methanol and 1,4-dioxane.

The reaction temperature will usually be from 0° C. to the refluxtemperature of the reaction solvent, and preferably from roomtemperature to the reflux temperature of the reaction solvent.

The reaction time will usually be from 0.1 to 72 hours, and preferablyfrom 0.5 to 12 hours.

Compound (24) obtained in this manner may be isolated and purified bypublicly known separation and purification means such as, for example,concentration, concentration under reduced pressure, solvent extraction,crystallization, reprecipitation or chromatography, or it may besupplied to the subsequent step without isolation and purification.

(Step 20) In this step, compound (24) obtained in the previous step isreacted with compound (25-1) or (25-2) to produce compound (26).

The reaction between compound (24) and compound (25-1) is a Mitsunobureaction, which may be carried out in the presence of a phosphinecompound and an azo compound, according to a method described in therelevant literature (for example, Mitsunobu, O., The use of diethylazodicarboxylate and triphenylphosphine in synthesis and transformationof natural products, Synthesis, Vol. 1, 1981, p1-28), a correspondingmethod, or a combination thereof with an ordinary method.

The amount of the alcohol compound (25-1) used in this step will usuallybe from 0.5 to 10 equivalents, and preferably from 1 to 3 equivalents,with respect to 1 equivalent of compound (24).

As examples of ordinary phosphine compounds to be used in this stepthere may be mentioned triphenylphosphine and triethylphosphine.

The amount of the phosphine compound to be used will usually be from 0.5to 10 equivalents, and preferably from 1 to 3 equivalents, with respectto 1 equivalent of compound (24).

As examples of azo compounds to be used there may be mentioned diethylazodicarboxylate and diisopropyl azodicarboxylate.

The amount of the azo compound to be used will usually be from 0.5 to 10equivalents, and preferably from 1 to 3 equivalents, with respect to 1equivalent of compound (24).

The reaction time in this step will usually be from 1 to 48 hours, andpreferably from 4 to 12 hours.

The reaction temperature in this step will usually be from 0° C. to thereflux temperature of the reaction solvent, and preferably from 15 to30° C.

The reaction solvent to be used in this step is not particularlyrestricted so long as it does not impede the reaction, and as specificexamples there may be mentioned tetrahydrofuran and toluene.

The reaction between compound (24) and compound (25-2) may be carriedout by the same method as in Step 2 above.

The number of equivalents of the halogen compound (25-2) with respect tocompound (24), and the reaction conditions such as the reactiontemperature, reaction time, etc. may be according to the method of Step2 above, a corresponding method, or a combination thereof with anordinary method.

Compound (26) may be produced by reaction between compound (24) and acompound represented by formula (25-3):R²²—X³   (25-3)[wherein R²² represents R² optionally having a substituent, and X³represents a leaving group such as mesylate or tosylate].

The number of equivalents of compound (25-3) with respect to compound(24), and the reaction conditions such as the reaction temperature,reaction time, etc. may be according to the method of Step 2 above, acorresponding method, or a combination thereof with an ordinary method.

Compound (26) obtained in this manner may be isolated and purified bypublicly known separation and purification means such as, for example,concentration, concentration under reduced pressure, crystallization,solvent extraction, reprecipitation or chromatography, or it may besupplied to the subsequent step without isolation and purification.

(Step 21) In this step, the protective group R for the carboxyl group ofcompound (26) obtained in the previous step is removed to producecompound (27).

This step may be carried out under the same reaction conditions as inStep 4 above, or by a method described in the relevant literature (forexample, Protective Groups in Organic Synthesis, T. W. Green, 2ndprinting, John Wiley & Sons, 1991), a corresponding method, or acombination thereof with an ordinary method.

Compound (27) obtained in this manner may be isolated and purified bypublicly known separation and purification means such as, for example,concentration, concentration under reduced pressure, solvent extraction,crystallization, reprecipitation or chromatography, or it may besupplied to the subsequent step without isolation and purification.

(Step 22) In this step, compound (27) obtained in the previous step isreacted with an amino compound (III) to produce compound (28).

This step is an amide bond-forming reaction, and the reaction conditionsincluding the reaction temperature and reaction solvent may be the sameas in Steps 5 and 10 above.

Compound (28) of the present invention which is obtained in this mannermay be isolated and purified by publicly known separation andpurification means such as, for example, concentration, concentrationunder reduced pressure, solvent extraction, crystallization,reprecipitation or chromatography.

When R²² in compound (28) has no protective group, compound (28) willcorrespond to a compound of the present invention.

Also, when a protective group is present on R²² and/or R³ of compound(28), the protective group may be removed to produce compound (I-5) ofthe present invention. Removal of the protective group may beaccomplished by a method described in the relevant literature (forexample, Protective Groups in Organic Synthesis, T. W. Green, 2ndprinting, John Wiley & Sons, 1991), a corresponding method, or acombination thereof with an ordinary method.

An example where a protective group is necessary is the case where thesubstituent on R² is hydroxy, and as an example of a protective groupfor hydroxy there may be mentioned tert-butyldimethylsilyl, which may beremoved using hydrochloric acid, trifluoroacetic acid, sodium hydroxide,tetrabutylammonium fluoride or the like.

As an example of one set of compounds for compound (20) to be used inStep 18 there may be mentioned compounds represented by the followingformula (22):

[wherein the symbols have the same definitions specified above], andthese compounds may be produced by the scheme illustrated below.

[where the symbols have the same definitions specified above]

(Step 18-1) In this step, a dihalopyridine compound (22-1) is reactedwith a sodium thioalkoxide to produce an alkylsulfanylpyridinederivative (22-2).

As specific examples of dihalopyridines to be used in this step theremay be mentioned 2,5-dibromopyridine, 2,5-dichloropyridine,2,5-diiodopyridine, 5-bromo-2-chloropyridine, 2-chloro-5-iodopyridineand 5-bromo-2-fluoropyridine.

The sodium thioalkoxide used in this step will usually be from 0.1 to 3equivalents, and preferably from 1 to 2 equivalents, with respect to 1equivalent of compound (22-1).

As specific examples of sodium thioalkoxides to be used there may bementioned sodium thiomethoxide, sodium thioethoxide, and the like.

The solvent used in this step may be, for example, an inert solvent,with no particular restrictions so long as it does not impede thereaction, and as specific examples there may be mentionedN,N-dimethylformamide, tetrahydrofuran, 1-methyl-2-pyrrolidinone, water,and the like.

The reaction time in this step will usually be from 0.5 to 72 hours, andpreferably from 1 to 12 hours.

Compound (22-2) obtained in this manner may be isolated and purified bypublicly known separation and purification means such as, for example,concentration, concentration under reduced pressure, crystallization,solvent extraction, reprecipitation or chromatography, or it may besupplied to the subsequent step without isolation and purification.

(Step 18-2) This step is a method of reacting compound (22-2) obtainedin Step 18-1 above with mCPBA to produce compound (22).

The oxidation reaction in this step may be carried out by the samemethod as in Step 3 described above, a corresponding method, or acombination thereof with an ordinary method.

The amount of mCPBA, the reaction temperature, the reaction time and thereaction solvent used in this step may be according to Step 3, oraccording to a corresponding method.

As oxidizing agents to be used in this step there may be mentionedhydrogen peroxide water, sodium tungstate, sodium hypochlorite and thelike.

The amount of oxidizing agent to be used in this step will usually befrom 0.1 to 10 equivalents, and preferably from 1 to 5 equivalents, withrespect to 1 equivalent of compound (22-2).

The solvent used for this step is not particularly restricted so long asit does not impede the reaction, and specifically there may be mentionedacetonitrile, ethanol, methanol, and the like.

Compound (22) obtained in this manner may be isolated and purified bypublicly known separation and purification means such as, for example,concentration, concentration under reduced pressure, crystallization,solvent extraction, reprecipitation or chromatography.

Compound (I-6) of the present invention may be produced by the followingscheme.

[wherein the symbols have the same definitions specified above]

(Step 24) In this step, compound (21) and compound (29) are reacted inthe presence of a base to produce compound (30).

X in compound (29) used for this step is a halogen atoms as definedabove, but more specifically there are preferred bromine and iodine.

Examples of groups for R in compound (29) used in this step includelower alkyl groups as defined above, but specifically there arepreferred methyl, ethyl, propyl and isopropyl.

As bases to be used in this step there may be mentioned potassiumphosphate, potassium acetate, potassium tert-butyrate, triethylamine andthe like.

The amount of the base used in this step will usually be from 0.01 to 10equivalents, and preferably from 0.1 to 2 equivalents, with respect to 1equivalent of compound (21).

Also, a palladium salt such as palladium (II) acetate or palladium (II)chloride and a ligand such as 2-(di-tert-butylphosphino)biphenyl ortriphenylphosphine may be copresent in the reaction system for thisstep.

The amount of the palladium salt used in this step will usually be from0.01 to 10 equivalents, and preferably from 0.1 to 2 equivalents, withrespect to 1 equivalent of compound (21).

The amount of the ligand used in this step will usually be from 0.1 to10 equivalents, and preferably from 0.5 to 2 equivalents with respect tocompound (21).

The reaction temperature will usually be from room temperature to thereflux temperature of the reaction solvent, and preferably from 50° C.to the reflux temperature of the reaction solvent.

The reaction solvent used may be any one which does not impede thereaction, and there may be mentioned, for example, toluene, 1,4-dioxane,N,N-dimethylformamide, tetrahydrofuran, 1-methyl-2-pyrrolidinone, andthe like.

The reaction time will usually be from 0.5 to 72 hours, and preferablyfrom 1 to 12 hours.

Compound (30) obtained in this manner may be isolated and purified bypublicly known separation and purification means such as, for example,concentration, concentration under reduced pressure, crystallization,solvent extraction, reprecipitation or chromatography, or it may besupplied to the subsequent step without isolation and purification.

(Step 25) In this step, the protective group R⁴ for the hydroxy group incompound (30) obtained in Step 24 above is removed to produce compound(31). The reaction for removal of the hydroxy group of compound (30) maybe carried out by a method described in the literature (for example,Protective Groups in Organic Synthesis, T. W. Green, 2nd printing, JohnWiley & Sons, 1991), a corresponding method, or a combination thereofwith an ordinary method, or alternatively the target compound may beproduced by the same method as in Step 19 above, a corresponding method,or a combination thereof with an ordinary method.

Compound (31) obtained in this manner may be isolated and purified bypublicly known separation and purification means such as, for example,concentration, concentration under reduced pressure, crystallization,solvent extraction, reprecipitation or chromatography, or it may besupplied to the subsequent step without isolation and purification.

(Step 26) In this step, compound (31) obtained in Step 25 above isreacted with R²²OH to produce compound (32).

The reaction carried out in this step is a Mitsunobu reaction, which maybe conducted in the presence of a phosphine compound and an azo compoundaccording to the aforementioned method described in the literature (forexample, Mitsunobu, O., The use of diethyl azodicarboxylate andtriphenylphosphine in synthesis and transformation of natural products,Synthesis, Vol. 1, 1981, p1-28), a corresponding method, or acombination thereof with an ordinary method.

The amount of the alcohol compound (25) used for this step will usuallybe from 0.5 to 10 equivalents, and preferably from 1 to 3 equivalents,with respect to 1 equivalent of compound (31).

As ordinary examples of phosphine compounds to be used for this stepthere may be mentioned triphenylphosphine and triethylphosphine.

The amount of the phosphine compound used will usually be from 0.5 to 10equivalents, and preferably from 1 to 3 equivalents, with respect to 1equivalent of compound (31).

As examples of azo compounds to be used there may be mentioned diethylazodicarboxylate, diisopropyl azodicarboxylate, and the like.

The amount of the azo compound used will usually be from 0.5 to 10equivalents, and preferably from 1 to 3 equivalents, with respect to 1equivalent of compound (31).

The reaction time in this step will usually be from 1 to 48 hours, andpreferably from 4 to 12 hours.

The reaction temperature in this step will usually be from 0° C. to thereflux temperature of the reaction solvent, and preferably from 15 to30° C.

The reaction solvent used in this step is not particularly restricted solong as it does not impede the reaction, and as specific examples theremay be mentioned tetrahydrofuran and toluene.

Compound (32) obtained in this manner may be isolated and purified bypublicly known separation and purification means such as, for example,concentration, concentration under reduced pressure, crystallization,solvent extraction, reprecipitation or chromatography, or it may besupplied to the subsequent step without isolation and purification.

(Step 27) In this step, the protective group for the carboxyl group ofcompound (32) above is removed to produce compound (33). This step maybe carried out by the same method as in Step 21, etc. described above, acorresponding method, or a combination thereof with an ordinary method.

Compound (33) obtained in this manner may be isolated and purified bypublicly known separation and purification means such as, for example,concentration, concentration under reduced pressure, crystallization,solvent extraction, reprecipitation or chromatography, or it may besupplied to the subsequent step without isolation and purification.

(Step 28) In this step, compound (33) obtained in Step 27 above isreacted with a compound represented by formula (a) to produce compound(34).

The reaction in this step is an amide bond-forming reaction, which maybe carried out by the same method as in Step 22 above, a correspondingmethod, or a combination thereof with an ordinary method.

Compound (34) obtained in this manner may be isolated and purified bypublicly known separation and purification means such as, for example,concentration, concentration under reduced pressure, crystallization,solvent extraction, reprecipitation or chromatography, or it may besupplied to the subsequent step without isolation and purification. Whenno protective group is present for R³ and/or R²² in compound (34),compound (34) corresponds to a compound of the present invention.

(Step 29) When R³ and/or R²² in compound (34) obtained in Step 28 abovehas a protective group, the protective group is appropriately removed inthis step to produce compound (I-5) of the present invention.

The reaction in this step may be conducted according to theaforementioned method described in the literature (for example,Protective Groups in Organic Synthesis, T. W. Green, 2nd printing, JohnWiley & Sons, 1991), a corresponding method, or a combination thereofwith an ordinary method.

Compound (I-5) obtained in this manner may be isolated and purified bypublicly known separation and purification means such as, for example,concentration, concentration under reduced pressure, crystallization,solvent extraction, reprecipitation or chromatography.

The heteroarylcarbamoylbenzene derivatives provided by the invention maybe in the form of pharmaceutically acceptable salts, and such salts maybe produced according to ordinary methods using compounds of formulas(I-1), (I-2), (I-3), (I-4), (I-5) and (I-6) above which are within thedefinition of compound (I) of the present invention.

Specifically, when the aforementioned compound (I-1), (I-2), (I-3),(I-4), (I-5) or (I-6) has a basic group derived from amino, pyridyl orthe like in the molecule, the compound may be treated with an acid forconversion to a corresponding pharmaceutically acceptable salt.

As examples of such acid addition salts there may be mentionedhydrohalides such as hydrochlorides, hydrofluorides, hydrobromides andhydroiodides; inorganic acid salts such as nitrates, perchlorates,sulfates, phosphates and carbonates; lower alkylsulfonates such asmethanesulfonates, trifluoromethanesulfonates and ethanesulfonates;arylsulfonates such as benzenesulfonates, p-toluenesulfonates; organicacid salts such as fumarates, succinates, citrates, tartrates, oxalatesand maleates; and acid addition salts with organic acids such as acidicamino acids, including glutamates and aspartates. When the compounds ofthe invention have acidic groups within such groups, for example, whenthey have carboxyl groups or the like, the compounds may be treated withbases for conversion to the corresponding pharmaceutically acceptablesalts. As examples of such base addition salts there may be mentionedsalts of alkali metals such as sodium and potassium, salts of alkalineearth metals such as calcium and magnesium, and salts of organic basessuch as ammonium salts, guanidine, triethylamine and dicyclohexylamine.The compounds of the invention may also be in the form of any desiredhydrates or solvates of the free compounds or their salts.

For production of a drug for prevention or treatment of type II diabetesor of a condition or symptoms associated therewith, the compound offormula (I) of the present invention may be used in combination with acarrier substance.

Needless to mention, the administered dosage for prevention or treatmentof a compound of formula (I) of the present invention will varydepending on the nature of the symptoms to be treated, the specificcompound selected, and the route of administration.

The dosage will also vary depending on the age, body weight andsensitivity of each patient. A daily dosage will generally be about0.001 mg to about 100 mg, preferably about 0.01 mg to about 50 mg andmore preferably about 0.1 mg to 10 mg per kilogram of body weight,either as a single dose or as divided doses. Dosages outside of theseranges may sometimes be necessary.

An example of an appropriate oral dosage is at least about 0.01 mg to amaximum of 2.0 g, either as a single dose or divided among 2 to 4multiple doses per day. The preferred dosage range is between about 1.0mg and about 200 mg per day, either by one or two administrations. Amore preferred dosage range is between about 10 mg and about 100 mg,administered as a single daily dose.

In the case of intravenous administration or oral administration, atypical dosage range is from about 0.001 mg to about 100 mg (preferablyfrom 0.01 mg to about 10 mg) of a compound of formula (I) per day perkilogram of body weight, and more preferably from about 0.1 mg to 10 mgof a compound of formula (I) per day per kilogram of body weight.

As mentioned above, the pharmaceutical composition comprises a compoundof formula (I) and a pharmaceutically acceptable carrier. The term“composition” refers to a product obtained by directly or indirectlycombining, compounding or aggregating two or more components, a productobtained as a result of dissociation of one or more components, or aproduct obtained as a result of any other type of action or interactionbetween components, and the term also includes the active and inactivecomponents (pharmaceutically acceptable excipients) composing thecarrier.

Preferred are compositions containing amounts of compounds of formula(I) effective for treating, preventing or delaying the onset of type IIdiabetes when used in combination with medically acceptable carriers.

An effective amount of a compound of the present invention may beadministered by any appropriate route of administration to mammals, andespecially humans. Examples of administration routes include oral,intrarectal, local, intravenous, ocular, pulmonary and nasal routes.Examples of dosage forms include tablets, lozenges, powdered agents,suspensions, solutions, capsules, creams and aerosols, among which oraltablets are preferred.

An oral composition may be prepared using any ordinary medicinal media,examples of which include water, glycol, oil, alcohol, aromaticadditives, preservatives, coloring agents and the like. Oral liquidcompositions may be prepared in the form of, for example, suspensions,elixirs and solutions, using starch, sucrose, microcrystallinecellulose, diluents, granulators, lubricants, binders, disintegratorsand the like as carriers, while oral solid compositions may be preparedin the form of, for example, powders, capsules, tablets or the like,among which oral solid compositions are preferred.

Tablets and capsules are the most advantageous oral dosage form becausethey are easy to administer. If necessary, tablets may be coated by astandard aqueous or non-aqueous technique.

In addition to the ordinary dosage forms mentioned above, the compoundsof formula (I) may also be administered by the controlled release meansand/or delivery devices described in, for example, U.S. Pat. Nos.3,845,770, 3,916,899, 3,536,809, 3,598,123, 3,630,200 and 4,008,719.

A pharmaceutical composition of the present invention which is suitablefor oral administration may be in the form of granules, tablets, orcapsules containing a predetermined amount of an active ingredientpowder or granules, as a water-soluble liquid or non-water-solubleliquid, or as an oil-in-water emulsion or a water-in-oil emulsion. Suchcompositions may be prepared by any pharmaceutical method, but allmethods involve combining an active ingredient with a carrier comprisingone or more necessary components.

Generally speaking, a composition may be prepared by uniformly andthoroughly mixing the active ingredient with a liquid carrier, with acompletely separated solid carrier, or both, and then shaping theproduct into an appropriate form if necessary. For example, tablets areprepared by compression and molding, together with one or more secondaryingredients as necessary. Compressed tablets are prepared by using anappropriate machine for admixture of the active ingredient in a powderor granular form with a binder, lubricant, inert excipient, surfactantor dispersing agent as necessary, and compressing the mixture.

Molded tablets are prepared by using an appropriate machine for moldingof a mixture of a wetted compound in powder form and an inert liquiddiluent.

Each tablet preferably contains from approximately 1 mg to 1 g of theactive ingredient, while granules or capsules preferably contain fromapproximately 1 mg to 500 mg of the active ingredient.

Examples of medicinal dosage forms for the compounds of formula (I) arelisted below. TABLE 1 Suspension for injection (I.M.) mg/ml Compound offormula (I) 10 Methyl cellulose 5.0 Tween80 0.5 Benzyl alcohol 9.0Benzalkonium chloride 1.0Water for injection added to 1.0 ml.

TABLE 2 Tablets mg/tablet Compound of formula (I) 25   Methyl cellulose415   Tween 80 14.0 Benzyl alcohol 43.5 Magnesium stearate  2.5 Total 500 mg

TABLE 3 Capsules mg/capsule Compound of formula (I) 25  Lactose powder573.5 Magnesium stearate  1.5 Total   600 mg

TABLE 4 Aerosol Per container Compound of Formula (I) 24 mg Lecithin, NFLiq. Conc. 1.2 mg Trichlorofluoromethane, NF 4.025 gDichlorodifluoromethane, NF 12.15 g

The compounds of formula (I) may be used not only for conditions orsymptoms associated with type II diabetes, but also in combination withother drugs applied for treatment, prevention or delay onset of type IIdiabetes. Such other drugs may be administered either simultaneously orseparately from the compound of formula (I), with ordinary routes ofadministration and dosages.

When the compound of formula (I) is used simultaneously with one or moredrugs, it is preferred to use a pharmaceutical composition comprisingthe compound of formula (I) and the other drugs. Thus, a pharmaceuticalcomposition of the present invention comprises a compound of formula (I)together with one or more other active ingredients. Examples of activeingredients to be used in combination with compounds of formula (I)include, but are not limited to, the following, which may beadministered separately or within the same pharmaceutical composition.

(a) Bisguanides (for example, buformin, metformin, phenformin),

(b) PPAR agonists (for example, troglitazone, pioglitazone,rosiglitazone),

(c) insulin,

(d) somatostatin,

(e) α-glucosidase inhibitors (for example, voglibose, miglitol,acarbose), and

(f) insulin secretagogues (for example, acetohexamide, carbutamide,chlorpropamide, glibomuride, gliclazide, glimerpiride, glipizide,gliquidine, glisoxepid, glyburide, glyhexamide, glypinamide,phenbutamide, tolazamide, tolbutamide, tolcyclamide, nateglinide,repaglinide).

The weight ratio of the compound of formula (I) with respect to anysecond active ingredient may be varied within a wide range, and willdepend on the effective amount of each active ingredient. For example,in the case of a combination of a compound of formula (I) with a PPARagonist, the weight ratio of the compound of formula (I) with respect tothe PPAR agonist will generally be from about 1000:1 to 1:1000, andpreferably from about 200:1 to 1:200. Combinations of a compound of theformula (I) and other active ingredients will also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used. The glucokinase activating power of thecompounds represented by compound (I) of the present invention, and thetest methods used, will now be explained.

The excellent glucokinase activating function of the compoundsrepresented by formula (I) above may be measured by a method describedin the relevant literature (for example, Diabetes, Vol. 45, pp.1671-1677, 1996) or by a corresponding method.

The glucokinase activity is the degree of activation of glucokinase, asdetermined not by direct measurement of glucose-6-phosphate, but bymeasurement of the amount of thio-NADH produced upon production ofphosphogluconolactone from glucose-6-phosphate by the reporter enzymeglucose-6-phosphate dehydrogenase.

The recombinant human liver GK used in this assay was expressed in E.coli as FLAG fusion protein, and it was purified by ANTIFLAG M2 AFFINITYGEL (Sigma).

The assay was carried out using a flat-bottomed 96-well plate at 30° C.A 69 μl portion of assay buffer (25 mM Hepes Buffer: pH=7.2, 2 mM MgCl₂,1 mM ATP, 0.5 mM TNAD, 1 mM dithiothreitol) was dispensed, and either aDMSO solution of the compound or 1 μl of DMSO as a control was added.Next, 20 μl of an enzyme mixture (FLAG-GK, 20 U/ml G6PDH) precooled inice bath was dispensed, and then 10 μl of 25 mM glucose was added assubstrate and reaction was initiated (final glucose concentration=2.5mM).

After initiation of the reaction, the increase in absorbance at 405 nmwas measured every 30 seconds during a 10 minute period, and theincrease during the first 5 minutes was used to evaluate the compound.FLAG-GK was added to produce an absorbance increment of from 0.05 to 0.1after 5 minutes in the presence of 1% DMSO.

The OD values were measured at each concentration of the evaluatedcompound, using the OD value of the DMSO control as 100%. The Emax (%)and EC50 (μM) values were calculated from the OD value at eachconcentration, and used as indices of the GK activating power of thecompounds.

The GK activating power of the compounds of the invention were measuredby this method. The results are shown in Table 1 below. TABLE 5 (GKactivating power of compounds of the invention) Compound No. Emax (%)EC50 (μM) Production 957 0.25 Example 1 Production 844 0.08 Example 2Production 936 0.53 Example 59

As shown in Table 1, the compounds of the invention exhibit excellent GKactivating power based on the Emax and EC50 values.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will now be explained in greater detail throughFormulation Examples and Production Examples, with the understandingthat the invention is in no way limited to these examples.

FORMULATION EXAMPLE 1

Ten parts of the compound of Production Example 1, 15 parts of heavymagnesium oxide and 75 parts of lactose were uniformly mixed to preparea pulverulent or fine granular powdered medicine with a size of nogreater than 350 μm. The powdered medicine was placed in capsulecontainers to prepare capsules.

FORMULATION EXAMPLE 2

Forty-five parts of the compound of Production Example 1, 15 parts ofstarch, 16 parts of lactose, 21 parts of microcrystalline cellulose, 3parts of polyvinyl alcohol and 30 parts of distilled water wereuniformly mixed, and the mixture was subsequently crushed, granulatedand dried and then filtered to prepare granules having sizes withdiameters of 1410 to 177 μm.

FORMULATION EXAMPLE 3

After preparing granules by the same method as in Formulation Example 2,3 parts of calcium stearate was added with respect to 96 parts of thegranules and the mixture was compression molded to form tablets withdiameters of 10 mm.

FORMULATION EXAMPLE 4

Ten parts of microcrystalline cellulose and 3 parts of calcium stearatewere added with respect to 90 parts of the granules obtained by themethod in Formulation Example 2, and the mixture was compression moldedto form tablets with diameters of 8 mm, after which a mixed suspensionof syrup gelatin and sedimentary calcium carbonate was added to preparesugar-coated tablets.

The present invention will now be explained in greater detail throughProduction Examples and Reference Examples, with the understanding thatthe invention is in no way limited to these examples.

The thin-layer chromatography carried out in the examples employedSilicagel 60F₂₄₅ (Merck) as the plate and a TV detector as the detectionmethod. The column silica gel used was Wakogel™ C-300 (Wako PureChemical Industries), and the reverse-phase column silica gel used wasLC-SORB™ SP-B-ODS (Chemco) or YMC-GEL™ ODS-AQ 120-S50 (Yamamura KagakuKenkyujo).

The abbreviations in the examples are explained below.

-   i-Bu: isobutyl-   n-Bu: n-butyl-   t-Bu: t-butyl-   Me: methyl-   Et: ethyl-   Ph: phenyl-   i-Pr: isopropyl-   n-Pr: n-propyl-   CDCl₃: heavy chloroform-   CD₃OD: heavy methanol-   DMSO-d₆: heavy dimethylsulfoxide

The abbreviations for the nuclear magnetic resonance spectra areexplained below.

-   s: singlet-   d: doublet-   dd: double doublet-   t: triplet-   m: multiplet-   br: broad-   q: quartet-   J: coupling constant-   Hz: Hertz

PRODUCTION EXAMPLE 1

Preparation of5-isopropoxy-3-(4-methanesulfonylphenoxy)-N-(4-methylthiazol-2-yl)-benzamide

After adding 29.0 g of molecular sieves 4A, 22.0 g (0.13 mol) ofp-methylthiophenylboric acid, 21.6 g (0.13 mol) of copper (II) acetateand 83.0 ml (0.59 mol) of triethylamine to a solution of 20.0 g (0.12mol) of 3,5-dihydroxybenzoic acid methyl ester in methylene chloride(1.2 l), the mixture was stirred at room temperature overnight under anoxygen atmosphere. The reaction mixture was filtered and thenconcentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography (hexane:acetic acid ethylester=2:1) to obtain 12.4 g of 5-hydroxy-3-(4-methylthiophenoxy)benzoicacid methyl ester (yield: 36%) as a yellow solid.

After adding 129 mg (0.94 mmol) of potassium carbonate and 0.053 ml(0.56 mmol) of 2-bromopropane to a solution of 54.4 mg (0.19 mmol) ofthe obtained phenolic compound in N,N-dimethylformamide (2.5 ml), thereaction mixture was stirred at 80° C. for 4 hours. Water was added tothe reaction mixture, extraction was performed with acetic acid ethylester, and then the organic layer was washed with brine, dried andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (hexane:acetic acid ethyl ester=2:1)to obtain 55.4 mg of 5-isopropoxy-3-(4-methylthiophenoxy)-benzoic acidmethyl ester (yield: 89%) as a colorless oil. After adding 64.0 mg (0.37mmol) of m-chloroperbenzoic acid to a solution of 41.0 mg (0.12 mmol) ofthe obtained ester compound in chloroform (2.0 ml) while cooling on ice,the reaction mixture was stirred for 20 minutes while cooling on ice.Aqueous sodium thiosulfate was added to the reaction mixture, and theorganic layer was washed with saturated aqueous sodium hydrogencarbonateand brine, dried, and concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (hexane:aceticacid ethyl ester=1:1) to obtain 43.9 mg of5-isopropoxy-3-(4-methanesulfonylphenoxy)-benzoic acid methyl ester(yield: 98%) as a colorless oil.

After adding 0.28 ml (0.56 mmol) of aqueous 2N sodium hydroxide to asolution of 41.0 mg (0.11 mmol) of the obtained sulfone compound inmethanol (1.0 ml), the reaction mixture was stirred overnight. Aqueous2N hydrochloric acid was added to the reaction mixture, extraction wasperformed with acetic acid ethyl ester, and the organic layer was washedwith brine, dried and concentrated under reduced pressure to obtain acrude carboxyl compound. After adding 5.90 mg (0.51 mol) of2-amino-4-methylthiazole, 9.30 mg (0.068 mmol) of 1-hydroxybenzotriazolehydrate and 13.0 mg (0.068 mol) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to asolution of 12.0 mg (0.034 mmol) of the obtained carboxyl compound inmethylene chloride (0.5 ml), the mixture was stirred at room temperatureovernight. The reaction mixture was concentrated under reduced pressure,and the obtained residue was purified by silica gel columnchromatography (hexane:acetic acid ethyl ester=1:1) to obtain the titlecompound as a white solid. The analysis data for the compound obtainedin Production Example 1 are shown below.

¹HNMR(CDCl₃)δ: 1.34(6H,d,J=6.0 Hz), 2.22(3H,d,J=0.7 Hz), 3.08(3H,s),4.53-4.57(1H,m), 6.57(1H,d,J=0.7Hz), 6.80(1H,t,J=2.0 Hz),7.11(1H,d,J=2.0 Hz), 7.12(2H,d,J=8.8 Hz), 7.27(1H,d,J=2.0 Hz),7.92(2H,d,J=8.8 Hz)

ESI-MS(m/e): 447[M+H]⁺

PRODUCTION EXAMPLE 2

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide

After adding 1.40 g (7.40 mmol) of(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and 2.00 g (7.40 mmol)of triphenylphosphine to a solution of 1.20 g (4.13 mmol) of the5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methyl ester obtained inProduction Example 1 in tetrahydrofuran (10 ml), 3.20 ml (7.40 mmol) ofdiethyl azodicarboxylate was added while cooling on ice, and the mixturewas stirred at room temperature for 2 hours. Water was added to thereaction mixture, extraction was performed with acetic acid ethyl ester,and then the organic layer was washed with brine, dried and concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (hexane:acetic acid ethyl ester=95:5) to obtain1.63 g of5-((1S)-2-(t-butyldimethylsiloxy)-1-methyl-ethoxy)-3-(4-methylthiophenoxy)-benzoicacid methyl ester (yield: 95%) as a colorless oil. After adding 2.06 g(12.0 mmol) of m-chloroperbenzoic acid to a solution of 1.84 g (3.97mmol) of the obtained ester compound in chloroform (40 ml) while coolingon ice, the reaction mixture was stirred for 0.5 hour while cooling onice. Aqueous sodium thiosulfate was added to the reaction mixture, andthe organic layer was washed with saturated aqueous sodiumhydrogencarbonate and brine, dried, and concentrated under reducedpressure to obtain a crude sulfone compound.

After adding 4.00 ml (20.0 mmol) of aqueous 5N sodium hydroxide to asolution of the obtained sulfone compound in methanol (20 ml), thereaction mixture was stirred for 1.5 hours. A 5% aqueous citric acidsolution (30 ml) was added to the reaction mixture, extraction wasperformed with acetic acid ethyl ester, and then the organic layer waswashed with brine, dried, and concentrated under reduced pressure toobtain a crude carboxyl compound. After adding 1.20 g (12.0 mmol) of2-aminothiazole, 1.62 g (12.0 mmol) of 1-hydroxybenzotriazole hydrateand 1.53 g (8.00 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride to a solution of the obtained a crude carboxyl compound inmethylene chloride (40 ml), the mixture was stirred at room temperatureovernight. The reaction mixture was then stirred for 1.5 hours. Waterwas added to the reaction mixture, extraction was performed with aceticacid ethyl ester, and the organic layer was washed with a 5% aqueouscitric acid, washed with brine, dried and concentrated under reducedpressure to obtain a crude amide compound.

After adding 20 ml of aqueous 4N hydrochloric acid to a solution of theobtained amide compound in 1,4-dioxane (60 ml), the mixture was stirredat room temperature for 15 minutes. The reaction mixture wasconcentrated under reduced pressure, and then triethylamine was addedand the reaction mixture was again concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography(hexane:acetic acid ethyl ester=1:2) to obtain the title compound as awhite solid. The analysis data for the compound obtained in ProductionExample 2 are shown below.

¹HNMR(CDCl₃)δ: 1.33(d,3H,J=6.2 Hz), 3.10(s,3H), 3.80(m,2H), 4.56(m, 1H),6.88(m,1H), 7.03(d,1H,J=3.6 Hz), 7.17(d,2H,J=8.8 Hz), 7.22(m,1H),7.38(m,2H), 7.96(d,2H,J=8.8 Hz), 10.8(br,1H),

ESI-MS(m/e): 449[M+H]⁺

Compounds for the following Production Examples 3 to 58 were obtained bythe same method as in Production Example 1 or 2 above. The structuresand analysis data for these compounds are shown below.

PRODUCTION EXAMPLE 3

Preparation of5-ethoxy-3-(4-methanesulfonylphenoxy)-N-(4-methoxymethyl-thiazol-2-yl)benzamide

The compound of Production Example 3 was obtained as a colorless oilusing the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methyl esterobtained in Production Example 1, bromoethane and2-amino-4-methoxymethyl-thiazole, by the same method as in ProductionExample 1, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 1.45(1H,t,J=7.0 Hz), 3.10(3H,s), 3.44(3H,s),4.10(2H,q,J=7.0 Hz), 4.45(2H,s), 6.85(1H,t,J=2.0 Hz), 6.92(1H,s),7.14(1H,s), 7.15(2H,d,J=8.8 Hz), 7.29(1H,s), 7.94(2H,d,J=8.8 Hz)

ESI-MS(m/e): 463[M+H]⁺

PRODUCTION EXAMPLE 4

Preparation of5-cyclopentyloxy-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide

The compound of Production Example 4 was obtained as a light yellow oilusing the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methyl esterobtained in Production Example 1, cyclopentyl bromide and2-amino-thiazole, by the same method as in Production Example 1, acorresponding method, or a combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.61-1.93(8H,m), 3.07(3H,s), 4.75-4.79(1H,m),6.81(1H,d,J=2.0 Hz), 6.97(1H,d,J=3.6 Hz), 7.13(2H,d,J=8.6 Hz),7.20(1H,s), 7.21(1H,d,J=3.6 Hz), 7.33(1H,d,J=2.0 Hz), 7.92(2H,d,J=8.6Hz)

ESI-MS(m/e): 459[M+H]⁺

PRODUCTION EXAMPLE 5

Preparation of3-(4-methanesulfonylphenoxy)-5-(tetrahydrofuran-3-yloxy)-N-thiazol-2-yl-benzamide

The compound of Production Example 5 was obtained as a light yellow oilusing the 5-hydroxy-3-4-methylthiophenoxy)benzoic acid methyl esterobtained in Production Example 1, 3-hydroxytetrahydrofuran and2-amino-thiazole, by the same method as in Production Example 2, acorresponding method, or a combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 2.14-2.27(2H,m), 3.08(3H,s), 3.91-3.99(4H,m),4.96-4.97(1H,d,J=1.7 Hz), 6.99(1H,d,J=3.6 Hz), 7.13(2H,d,J=8.9 Hz),7.18(1H,d,J=3.6 Hz), 7.25(1H,s), 7.30(1H,d,J=1.7 Hz), 7.93(2H,d,J=8.9Hz)

ESI-MS(m/e): 461[M+H]⁺

PRODUCTION EXAMPLE 6

Preparation of3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide

The compound of Production Example 6 was obtained as a colorlessamorphous substance using the 5-hydroxy-3-(4-methylthiophenoxy)benzoicacid methyl ester obtained in Production Example 1,1-methoxy-2-hydroxy-propane and 2-amino-thiazole, by the same method asin Production Example 2, a corresponding method, or a combinationthereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.31(d, 3H,J=6.3 Hz), 3.07(s,3H), 3.38(s,3H), 3.55(m,2H),4.59(m,1H), 6.89(m,1H), 6.98(d,1H,J=3.6 Hz), 7.13(d,2H,J=8.8 Hz),7.22(m,1H), 7.25(d,1H,J=3.6 Hz), 7.38(m,1H), 7.92(d,2H,J=8.8 Hz)

ESI-MS(m/e): 463[M+H]⁺

PRODUCTION EXAMPLE 7

Preparation of3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methoxymethyl-ethoxy)-N-thiazol-2-yl-benzamide

The compound of Production Example 7 was obtained as a colorlessamorphous substance using the 5-hydroxy-3-(4-methylthiophenoxy)benzoicacid methyl ester obtained in Production Example 1,1,3-dimethoxy-2-hydroxy-propane and 2-aminothiazole, by the same methodas in Production Example 2, a corresponding method, or a combinationthereof with an ordinary method.

¹HNMR(CDCl₃)δ: 3.08(s,3H), 3.39(s,6H), 3.63(d,4H,J=4.7 Hz), 4.57(m,1H),6.98(m,2H), 7.15(d,2H,J=8.9 Hz), 7.27(m,2H), 7.45(m,1H), 7.93(d,2H,J=8.9Hz)

ESI-MS(m/e): 493[M+H]⁺

PRODUCTION EXAMPLE 8

Preparation of3-(2-fluoro-4-methanesulfonylphenoxy)-5-isopropoxy-N-thiazol-2-yl-benzamide

The compound of Production Example 8 was obtained as a light yellow oilusing 5-hydroxy-3-(2-fluoro4-methanesulfonylphenoxy)benzoic acid methylester obtained in the same manner as Production Example 1,2-bromopropane and 2-amino-thiazole, by the same method as in ProductionExample 1, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 1.37(6H,d,J=6.1 Hz), 3.11(3H,s), 4.60-4.64(1H,m),6.81(1H,t,J=2.2 Hz), 7.02(1H,d,J=3.6 Hz), 7.15(1H,t,J=2.2 Hz),7.21(1H,dd,J=7.5,8.5 Hz), 7.31(1H,t,J=2.2 Hz), 7.40(1H,d,J=3.6 Hz),7.72(1H,ddd,J=1.2,2.2,7.5 Hz)

ESI-MS(m/e): 451 [M+H]⁺

PRODUCTION EXAMPLE 9

Preparation of3-(4-methanesulfonylphenoxy)-5-(1-methoxymethyl-propoxy)-N-(4-methyl-thiazol-2-yl)-benzamide

The compound of Production Example 9 was obtained as a white amorphoussubstance using the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methylester obtained in Production Example 1, 2-hydroxy-1-methoxy-butane and2-amino-4-methyl-thiazole, by the same method as in Production Example2, a corresponding method, or a combination thereof with an ordinarymethod.

¹HNMR(CDCl₃)δ: 0.97(t,3H,J=7.3 Hz), 1.71(quintet,2H,J=7.3 Hz),2.23(s,3H), 3.08(s,3H), 3.36(s,3H), 3.54(m,2H), 4.32(m,1H), 6.56(s,1H),6.90(m,1H), 7.13(d,2H,J=8.9 Hz), 7.15(m,1H), 7.35(m,1H), 7.92(d,2H,J=8.9Hz), 10.6(br,1H)

ESI-MS(m/e): 491[M+H]⁺

PRODUCTION EXAMPLE 10

Preparation of5-isopropoxy-3-(4-methanesulfonylphenoxy)-N-pyrazol-3-yl-benzamide

The compound of Production Example 10 was obtained as a light yellow oilusing the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methyl esterobtained in Production Example 1, 2-bromopropane and 3-aminopyrazole, bythe same method as in Production Example 1, a corresponding method, or acombination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.35(d,6H,J=6.0 Hz), 3.06(s,3H), 4.58(septet,1H,J=6.0Hz), 6.00(d,1H,J=3.0 Hz), 6.78(m,1H), 7.15(d,2H,J=8.9 Hz), 7.32(m,1H),7.41(m,1H), 7.90(d,2H,J=8.9 Hz), 8.14(d,1H,J=3.0 Hz)

ESI-MS(m/e): 416[M+H]⁺

PRODUCTION EXAMPLE 11

Preparation of5-isopropoxy-3-(4-methanesulfonylphenoxy)-N-pyrazin-2-yl-benzamide

The compound of Production Example 11 was obtained as a white amorphoussubstance using the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methylester obtained in Production Example 1, 2-bromopropane and2-aminopyrazine, by the same method as in Production Example 1, acorresponding method, or a combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.39(d,6H,J=6.0 Hz), 3.09(s,3H), 4.62(septet, 1H,J=6.0Hz), 6.82(m,1H), 7.14(m,1H), 7.17(d,2H,J=8.6 Hz), 7.39(m,1H),7.95(d,2H,8.6 Hz), 8.30(m,1H), 8.41(m,2H), 9.68(brs,1H)

ESI-MS(m/e): 428[M+H]⁺

PRODUCTION EXAMPLE 12

Preparation of3-(4-methanesulfonylphenoxy)-5-(3-methoxy-1-methyl-propoxy)-N-thiazol-2-yl-benzamide

The compound of Production Example 12 was obtained as a white amorphoussubstance using the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methylester obtained in Production Example 1, 2-bromo-4-methoxybutane and2-aminothiazole, by the same method as in Production Example 1, acorresponding method, or a combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.34(d,3H,J=6.1 Hz), 1.87(m,1H), 2.02(m,1H), 3.07(s,3H),3.32(s,3H), 3.50(m,2H), 4.61(m,1H), 6.87(m,1H), 6.98(d,1H,J=3.4 Hz),7.14(d,2H,J=8.8Hz), 7.21(m,1H), 7.25(d,1H,J=3.4 Hz), 7.39(m,1H),7.92(d,2H,J=8.8 Hz), 11.6(br,1H)

ESI-MS(m/e): 477[M+H]⁺

PRODUCTION EXAMPLE 13

Preparation of5-(3-hydroxy-1-methyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide

The compound of Production Example 13 was obtained as a white amorphoussubstance using the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methylester obtained in Production Example 1,1-(tert-butyldimethylsiloxy)-3-hydroxy-butane and 2-amino-thiazole, bythe same method as in Production Example 2, a corresponding method, or acombination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.39(d,3H,J=6.1 Hz), 1.88(m,1H), 2.02(m,1H), 3.10(s,3H),3.84(m,2H), 4.71(m,1H), 6.88(m,1H), 7.01(d,1H,J=3.5 Hz), 7.17(d,2H,J=8.9Hz), 7.24(m,1H), 7.35(d,1H,J=3.5 Hz), 7.48(m,1H), 7.95(d,2H,J=8.9 Hz),11.0(br, 1H)

ESI-MS(m/e): 463[M+H]⁺

PRODUCTION EXAMPLE 14

Preparation of5-isopropoxy-3-(4-methanesulfonylphenoxy)-N-pyrimidin-4-yl-benzamide

The compound of Production Example 14 was obtained as a white amorphoussubstance using the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methylester obtained in Production Example 1, 2-bromopropane and4-amino-pyrazine, by the same method as in Production Example 1, acorresponding method, or a combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.38(d,6H,J=6.0 Hz), 3.90(s,3H), 4.63(septet,1H,J=6.0Hz), 6.83(m,1H), 7.16(m,1H), 7.16(d,2H,J=8.9 Hz), 7.29(m,1H),7.95(d,2H,J=8.9 Hz), 8.31(dd,1H,J=1.2,5.6 Hz), 8.61(br,1H), 8.70(d,1H,J=5.6 Hz), 8.90(d,1H,J=1.2 Hz)

ESI-MS(m/e): 428[M+H]⁺

PRODUCTION EXAMPLE 15

Preparation of5-isopropoxy-3-(4-methanesulfonylphenoxy)-N-(pyrimidin-2-yl)-benzamide

The compound of Production Example 15 was obtained as a white amorphoussubstance using the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methylester obtained in Production Example 1, 2-bromopropane and2-amino-pyrazine, by the same method as in Production Example 1, acorresponding method, or a combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.37(d,6H,J=6.0 Hz), 3.08(s,3H), 4.62(septet,1H,J=6.0Hz), 6.79(t,1H,J=2.2 Hz), 7.05-7.20(m,4H).7.31(t,1H,J=2.2 Hz),7.93(d,2H,J=8.8 Hz), 8.60(br,1H), 8.68(d,2H,J=5.9 Hz)

ESI-MS(m/e): 428[M+H]⁺

PRODUCTION EXAMPLE 16

Preparation ofN-(4-hydroxymethyl-thiazol-2-yl)-5-isopropoxy-3-(4-methanesulfonylphenoxy)-benzamide

The compound of Production Example 16 was obtained as a white amorphoussubstance using the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methylester obtained in Production Example 1, 2-bromopropane and2-amino-4-(tert-butyldimethylsiloxymethyl)-thiazole, by the same methodas in Production Example 1, a corresponding method, or a combinationthereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.38(6H,d,J=6.0 Hz), 3.08(3H,s), 4.61-4.65(3H,m),6.83(1H,t,J=2.2 Hz), 6.87(1H,s), 7.17(2H,d,J=8.9 Hz), 7.18(1H,d,J=2.0Hz), 7.34(1H,d,J=2.0 Hz), 7.95(2H,d,J=8.9 Hz)

ESI-MS(m/e): 463[M+H]⁺

PRODUCTION EXAMPLE 17

Preparation ofN-(isooxazol-3-yl)-3-(4-methanesulfonylphenoxy)-5-(1-methoxymethyl-propoxy)-benzamide

The compound of Production Example 17 was obtained as a colorless oilusing the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methyl esterobtained in Production Example 1, 2-hydroxy-1-methoxy-butane and3-amino-oxazole, by the same method as in Production Example 2, acorresponding method, or a combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 0.99(t,3H,J=7.5 Hz), 1.74(quintet,2H,J=7.5 Hz),3.01(s,3H), 3.38(s,3H), 3.57(m,2H), 4.39(m,1H), 6.89(m,1H),7.16-7.12(m,2H), 7.14(d,2H,J=8.8 Hz), 7.32(m,1H), 7.93(d,2H,J=8.8 Hz),8.33(s,1H,J=1.9 Hz), 8.64(br,1H)

ESI-MS(m/e): 461[M+H]⁺

PRODUCTION EXAMPLE 18

Preparation of3-(4-methanesulfonylphenoxy)-5-(1-methoxymethyl-propoxy)-N-[1,3,4]thiadiazol-2-yl-benzamide

The compound of Production Example 18 was obtained as a colorless oilusing the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methyl esterobtained in Production Example 1, 2-hydroxy-1-methoxy-butane and2-amino-1,3,4-thiadiazole, by the same method as in Production Example2, a corresponding method, or a combination thereof with an ordinarymethod.

¹HNMR(CDCl₃)δ: 0.98(t,3H,J=7.5 Hz), 1.75(quintet,2H,J=7.5 Hz),3.07(s,3H), 3.37(s,3H), 3.56(m,2H), 4.45(m,1H), 6.93(m,1H),7.14(d,2H,J=8.9 Hz), 7.44(m,1H), 7.53(m,1H), 7.91(d,2H,J=8.9 Hz),8.73(s,1H), 12.0(br,1H)

ESI-MS(m/e): 478[M+H]⁺

PRODUCTION EXAMPLE 19

Preparation of5-(1-hydroxymethyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-(4-methyl-thiazol-2-yl)-benzamide

The compound of Production Example 19 was obtained as a colorlessamorphous substance using the 5-hydroxy-3-(4-methylthiophenoxy)benzoicacid methyl ester obtained in Production Example 1,1-(tert-butyldimethylsiloxy)-2-hydroxy-butane and2-amino-4-methyl-thiazole, by the same method as in Production Example2, a corresponding method, or a combination thereof with an ordinarymethod.

¹HNMR(CDCl₃)δ: 0.99(t,3H,J=7.3 Hz), 1.68(m,2H), 2.28(d,3H,J=1.0 Hz),3.09(s,3H), 3.82(m,2H), 4.36(m,1H), 6.57(d,1H,J=1.0 Hz), 6.75(m,1H),7.11(m,1H), 7.13(d,2H,J=8.9Hz), 7.28(m,1H), 7.93(d,2H,J=8.9 Hz),10.8(br,1H)

ESI-MS(m/e): 477[M+H]⁺

PRODUCTION EXAMPLE 20

Preparation ofN-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methanesulfonylphenoxy)-5-(1-methoxymethyl-propoxy)-benzamide

The compound of Production Example 20 was obtained as a white amorphoussubstance using the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methylester obtained in Production Example 1, 2-hydroxy-1-methoxy-butane and2-amino-4-(tert-butyldimethylsiloxymethyl)-thiazole, by the same methodas in Production Example 2, a corresponding method, or a combinationthereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.01(t,3H,J=7.5 Hz), 1.76(quintet,2H,J=7.5 Hz),3.10(s,3H), 3.40(s,3H), 3.59(m,2H), 4.43(m,1H), 4.64(s,2H), 6.89(s,1H),6.94(m,1H), 7.18(d,2H,J=9.0 Hz), 7.20(m,1H), 7.40(m,1H), 7.96(d,2H,J=9.0Hz), 10.0(br,1H)

ESI-MS(m/e): 507[M+H]⁺

PRODUCTION EXAMPLE 21

Preparation of5-(2-amino-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide

The compound of Production Example 21 was obtained as a white amorphoussubstance using the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methylester obtained in Production Example 1,1-(tert-butoxycarbonylamino)-2-hydroxy-propane and 2-aminothiazole, bythe same method as in Production Example 2, a corresponding method, or acombination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.30(d,3H,J=6.0 Hz), 2.92(d,2H,J=6.0 Hz), 3.09(s,3H),4.41(sextet,1H,J=6.0 Hz), 6.86(m,1H), 6.98(d,1H,J=3.5 Hz),7.14(d,2H,J=8.9 Hz), 7.21(d,1H,J=3.5 Hz), 7.25(m,1H),7.42(m,1H)8.87(d,2H,J=8.9 Hz)

ESI-MS(m/e): 448[M+H]⁺

PRODUCTION EXAMPLE 22

Preparation of5-(2-dimethylamino-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide

The compound of Production Example 22 was obtained as a light yellow oilusing the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methyl esterobtained in Production Example 1, 1-dimethylamino-2-hydroxypropane and2-amino-thiazole, by the same method as in Production Example 2, acorresponding method, or a combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ 1.28(d,3H,J=6.2 Hz), 2.30(s,6H), 2.42(dd, 1H,J=4.4,13.0Hz), 2.68(dd,1H,J=6.2 Hz,13.0 Hz), 3.09(s,3H), 4.56(dt, 1H,J=4.5,6.2Hz), 6.89(m,1H), 7.00(d,1H,J=3.6 Hz), 7.15(d,2H,J=8.9 Hz), 7.22(m,1H),7.28(d,1H,3.6 Hz), 7.41(m,1H), 7.93(d,2H,J=8.9 Hz), 11.4(br,1H)

ESI-MS(n/e): 476[M+H]⁺

PRODUCTION EXAMPLE 23

Preparation of5-(2-hydroxy-propoxy)-3-(4-methanesulfonylphenoxy)-N-(4-methyl-thiazol-2-yl)-benzamide

The compound of Production Example 23 was obtained as a white amorphoussubstance using the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methylester obtained in Production Example 1,2-(tert-butyldimethylsiloxy)-1-hydroxy-propane and2-amino-4-methylthiazole, by the same method as in Production Example 2,a corresponding method, or a combination thereof with an ordinarymethod.

¹HNMR(CDCl₃)δ: 1.28(d,3H,J=6.4 Hz), 2.20(d,3H,J=1.0 Hz), 3.08(s,3H),3.79(m,1H), 3.93(m,1H), 4.20(m,1H), 6.57(d,1H,J=1.0 Hz), 6.78(m,1H),7.09(d,2H,J=8.9 Hz), 7.16(m,1H), 7.25(m,1H), 7.92(d,2H,J=8.9 Hz),11.2(br,1H)

ESI-MS(m/e): 463[M+H]⁺

PRODUCTION EXAMPLE 24

Preparation of3-(4-methanesulfonylphenoxy)-5-(2-methoxy-propoxy)-N-(4-methyl-thiazol-2-yl)-benzamide

The compound of Production Example 24 was obtained as a colorless oilusing the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methyl esterobtained in Production Example 1, 1-hydroxy-2-methoxy-propane and2-amino-4-methylthiazole, by the same method as in Production Example 2,a corresponding method, or a combination thereof with an ordinarymethod.

¹HNMR(CDCl₃)δ: 1.26(d,3H,J=6.3 Hz), 2.22(d,3H,J=1.1 Hz), 3.08(s,3H),3.43(s,3H), 3.72(m,1H), 3.93(m,2H), 6.57(d,1H,J=1.1 Hz), 6.86(m,1H),7.12(d,2H,J=8.6 Hz), 7.16(m,1H), 7.29(m,1H), 7.92(d,2H,J=8.6 Hz),10.6(br,1H)

ESI-MS(m/e): 477[M+H]⁺

PRODUCTION EXAMPLE 25

Preparation of5-isopropoxy-3-(4-methanesulfonylphenoxy)-N-(thiazolo[5,4-b]pyridin-2-yl)-benzamide

The compound of Production Example 25 was obtained as a light yellowsolid using the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methylester obtained in Production Example 1, 2-bromopropane and2-amino-thiazolo[5,4-b]pyridine, by the same method as in ProductionExample 1, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 1.37(6H,d,J=6.0 Hz), 3.09(3H,s), 4.59-4.63(1H,m),6.84(1H,t,J=1.8 Hz), 7.14(2H,d,J=8.9 Hz), 7.19(1H,t,J=1.8 Hz),7.34(1H,t,J=1.8 Hz), 7.38(1H,dd,J=4.7,8.1 Hz), 7.92(1H,dd,J=1.5,8.1 Hz),7.94(2H,d,J=8.9 Hz), 8.53(1H,dd,J=1.5,4.7 Hz)

ESI-MS(m/e): 484[M+H]⁺

PRODUCTION EXAMPLE 26

Preparation of5-(2-hydroxymethyl-allyl)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide

¹HNMR(CDCl₃)δ: 3.08(3H,s), 3.49(2H,s), 4.06(2H,s), 4.91(1H,s),5.19(1H,s), 7.00 (1H,d,J=3.3 Hz), 7.11(2H,d,J=9.0 Hz), 7.13(1H,d,J=3.3Hz), 7.20(1H,s), 7.55(1H,s), 7.67(1H,s), 7.92(2H,d,J=9.0 Hz)

ESI-MS(m/e): 445[M+H]⁺

PRODUCTION EXAMPLE 27

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazolo[5,4-b]pyridin-2-yl-benzamide

The compound of Production Example 27 was obtained as a light yellowsolid using the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methylester obtained in Production Example 1,1-(tert-butyldimethylsiloxy)-2-hydroxypropane and2-amino-thiazolo[5,4-b]pyridine, by the same method as in ProductionExample 2, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 1.34(6H,d,J=6.2 Hz), 3.11(3H,s), 3.74(2H,d,J=4.6 Hz),4.57-4.62(1H,m), 6.92(1H,t,J=1.8 Hz), 7.19(2H,d,J=8.9 Hz),7.36(1H,t,J=1.8 Hz), 7.43(1H,dd,J=4.7,8.2 Hz), 7.49(1H,t,J=1.8 Hz),7.94(2H,d,J=8.9 Hz), 8.03(1H,dd,J=1.4,8.2 Hz), 8.49(1H,dd,J=1.4,4.7 Hz)

ESI-MS(m/e): 484[M+H]⁺

PRODUCTION EXAMPLE 28

Preparation of5-(3-hydroxy-2-methyl-propyl)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide

¹HNMR(CDCl₃)δ: 0.94(6H,d,J=6.7 Hz), 1.97-2.05(1H,m), 2.50-2.94(2H,m),3.08(3H,s), 3.50-3.56(2H,m), 7.03(1H,d,J=3.5 Hz), 7.13(2H,d,J=8.8 Hz),7.17(1H,s), 7.42(1H,d,J=3.5 Hz), 7.52(1H,s), 7.63(1H,s), 7.93(2H,d,J=8.8Hz)

ESI-MS(m/e): 447[M+H]⁺

PRODUCTION EXAMPLE 29

Preparation of3-(4-methanesulfonylphenoxy)-N-(4-methyl-thiazol-2-yl)-5-(piperidin-4-yl-oxy)-benzamidehydrochloride

The compound of Production Example 29 was obtained as white crystalsusing the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methyl esterobtained in Production Example 1,1-(tert-butoxycarbonyl)-4-hydroxy-piperidine and2-amino-4-methyl-thiazole, by the same method as in Production Example2, a corresponding method, or a combination thereof with an ordinarymethod.

¹HNMR(CD₃OD)δ: 1.93(m,2H), 2.11(m,2H), 2.31(s,3H), 2.99(s,3H),3.13(m,2H), 3.30(m,2H), 4.75(m,1H), 6.89(s,1H), 7.11(m,2H,J=8.9 Hz),7.27(m,1H), 7.52(m,1H), 7.84(d,2H,J=8.9 Hz)

PRODUCTION EXAMPLE 30

Preparation of5-(1-acetyl-piperidin-4-yloxy)-3-(4-methanesulfonylphenoxy)-N-(4-methyl-thiazol-2-yl)-benzamide

The compound of Production Example 30 was obtained as a white amorphoussubstance using the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methylester obtained in Production Example 1, 1-acetyl4-hydroxy-piperidine and2-amino4-thiazole, by the same method as in Production Example 2, acorresponding method, or a combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.80(m,3H), 2.20-2.00(m,2H), 2.14(s,3H), 2.51(s,3H), 3.10(s,3H), 3.50(m,1H), 3.75(m,1H), 4.01(m,1H), 4.84(m,1H), 4.84(m,1H),6.71(s,1H), 6.92(m,1H), 7.18(d,2H,J=8.9 Hz), 7.43(m,1H), 7.76(m,1H),7.96(d,2H,J=8.9 Hz)

ESI-MS(m/e): 530[M+H]⁺

PRODUCTION EXAMPLE 31

Preparation of2-[3-(4-methanesulfonylphenoxy)-5-(4-methyl-thiazol-2-yl-carbamoyl)-phenoxy]propionicacid

The compound of Production Example 31 was obtained as white crystalsusing the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methyl esterobtained in Production Example 1, 2-bromopropionic acid tert-butyl esterand 2-amino-4-methyl-thiazole, by the same method as in ProductionExample 1, a corresponding method, or a combination thereof with anordinary method. The method of removing the tert-butyl group serving asthe protective group for the carboxyl group for production of thiscompound may be a method described in the relevant literature (forexample, Protective Groups in Organic Synthesis, T. W. Green, 2ndprinting, John Wiley & Sons, 1991), a corresponding method, or acombination thereof with an ordinary method.

¹HNMR(DMSO-d₆)δ: 1.53(d,3H,J=6.8 Hz), 2.28(s,3H), 3.27(s,3H),5.03(septet,1H,J=6.8 Hz), 6.82(m,1H), 6.94(m,1H), 7.25(d,2H,J=8.8 Hz),7.42(m,1H), 7.50(m,1H), 7.95(d,2H,J=8.8 Hz)

ESI-MS(m/e): 477[M+H]⁺

PRODUCTION EXAMPLE 32

Preparation of5-(3-hydroxy-1-methyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide

The compound of Production Example 32 was obtained as a white amorphoussubstance using the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methylester obtained in Production Example 1,1-(tert-butyldimethylsiloxy-3-hydroxybutane and 2-aminothiazole, by thesame method as in Production Example 2, a corresponding method, or acombination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.35(d,3H,J=6.0 Hz), 1.83(m,1H), 2.00(m,1H), 3.08(s,3H),3.78(m,2H), 4.65(m,1H), 6.86(m,1H), 6.98(m,1H,J=3.5 Hz), 7.13(d,2H,J=8.8Hz), 7.21(d,1H,J=3.5 Hz), 7.23(m,1H), 7.45(m,1H,), 7.91(d,2H,J=8.8 Hz),12.1(br,1H)

ESI-MS(m/e): 463[M+H]⁺

PRODUCTION EXAMPLE 33

Preparation of3-(4-methanesulfonylphenoxy)-5-(1-methylcarbamoyl-ethoxy)-N-(4-methyl-thiazol-2-yl)-benzamide

The compound of Production Example 33 was obtained as a white amorphoussubstance by reaction between the2-[3-(4-methanesulfonylphenoxy)-5-(4-methyl-thiazol-2-yl-carbamoyl)-phenoxy]propionicacid obtained in Production Example 31 and methylamine. The reactionbetween the compound obtained in Production Example 31 and methylamineis an amide bond-forming reaction, by a method described in the relevantliterature (for example, Peptide Gosei no Kiso to Jikken, Izumiya, N. etal., Maruzen Publ., 1983, Comprehensive Organic Synthesis, Vol. 6,Pergamon Press, 1991), a corresponding method, or a combination thereofwith an ordinary method.

¹HNMR(CDCl₃)δ: 1.59(s,3H), 2.26(s,3H), 2.86(d,3H,J=4.7 Hz), 3.10(s,3H),4.73(q,1H,J=6.6 Hz), 6.47(br,1H), 6.57(m,1H), 6.83(m,1H),7.12(d,2H,J=8.8 Hz), 7.22(m,1H), 7.31(m,1H), 7.93(d,2H,J=8.8 Hz),11.0(br,1H)

ESI-MS(m/e): 490[M+H]⁺

PRODUCTION EXAMPLE 34

Preparation of5-(2-acetylamino-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide

The compound of Production Example 34 was obtained as a white amorphoussubstance by reaction between acetic acid and5-(2-amino-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-N-thiazol-2-yl-benzamideobtained by converting the hydroxy group of the5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-N-thiazol-2-yl-benzamideobtained in Production Example 2 to an amino group.

The reaction for conversion from the hydroxy group to an amino group maybe accomplished by converting the hydroxy group to a mesyl group, andthen reacting the mesyl compound with sodium azide to produce an azidecompound, and reducing the azide group with triphenylphosphine or thelike. The conversion reaction may be carried out by the method describedin Comprehensive Organic Transformations, Richard C. Larock, 2ndprinting, John Wiley & Sons, 1999), a corresponding method, or acombination thereof with an ordinary method.

The reaction between the3-(2-amino-1-methyl-ethoxy)-5-(4-methanesulfonyl-phenoxy)-N-thiazol-2-yl-benzamideand acetic acid is an amide bond-forming reaction, and it may be carriedout by the same method as the amide bond-forming reaction used in Step 1or another step, a corresponding method, or a combination thereof withan ordinary method.

¹HNMR(CDCl₃)δ: 1.33(d,3H,J=6.0 Hz), 2.03(s,3H), 3.10(s,3H),3.49(t,2H,J=5.8 Hz), 4.56(sextet, 1H,J=6.0 Hz), 5.98(t, 1H,J=5.8 Hz),6.87(m,1H), 7.00(d, 1H,J=3.6Hz), 7.15(d,2H,J=8.7 Hz), 7.28(m,2H),7.54(m,1H), 7.94(d,2H,J=8.7 Hz), 11.9(br,1H)

ESI-MS(m/e): 490[M+H]⁺

PRODUCTION EXAMPLE 35

Preparation ofN-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-5-isopropoxy-3-(4-methanesulfonylphenoxy)-benzamide

The compound of Production Example 35 was obtained as a white solidusing the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methyl esterobtained in Production Example 1, 2-bromopropane and2-amino-4-(1-tertbutyldimethylsiloxy-ethyl)-thiazole, by the same methodas in Production Example 1, a corresponding method, or a combinationthereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.38(6H,d,J=6.0 Hz), 1.55-1.60(3H,br), 3.08(3H,s),4.63(1H,quint,J=6.0 Hz), 4.90(1H,q,J=6.6 Hz), 6.79-6.85(2H,m),7.16(2H,d,J=8.8 Hz), 7.20(1H,br), 7.36(1H,br), 7.94(2H,d,J=8.8 Hz)

ESI-MS(m/e): 477[M+H]⁺

PRODUCTION EXAMPLE 36

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-pyridin-2-yl-benzamide

The compound of Production Example 36 was obtained as white crystalsusing the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methyl esterobtained in Production Example 1,1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 2-aminopyridine, bythe same method as in Production Example 2, a corresponding method, or acombination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.32(3H,d,J=3.2 Hz), 3.08(3H,s), 3.76-3.79(2H,m),4.57-4.63(1H,m), 6.48(1H,t,J=2.0 Hz), 7.13-7.17(1H,m), 7.15(2H,d,J=8.8Hz), 7.18(1H,d,J=2.0 Hz), 7.35(1H,d,J=2.0 Hz), 7.76(1H,ddd,J=1.6,5.1,8.4Hz), 7.93(2H,d,J=8.8 Hz), 8.30(1H,d,J=5.1 Hz), 8.34(1H,d,J=8.4 Hz),

ESI-MS(m/e): 443[M+H]⁺

PRODUCTION EXAMPLE 37

Preparation of5-(2-hydroxy-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide

The compound of Production Example 37 was obtained as a white amorphoussubstance using the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methylester obtained in Production Example 1,1-(tert-dimethylbutylsiloxy)-2-hydroxyethane and 2-aminothiazole, by thesame method as in Production Example 2, a corresponding method, or acombination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 3.10(s,3H), 4.01(t,2H,J=4.5 Hz), 4.14(t,2H,J=4.5 Hz),6.87(m,1H), 7.02(d,1H,J=3.0 Hz), 7.16(d,2H,J=8.4 Hz), 7.30(m,2H),7.38(m,1H), 7.95(d,2H,J=8.4 Hz), 11.3(br,1H)

ESI-MS(m/e): 435[M+H]⁺

PRODUCTION EXAMPLE 38

Preparation of5-(2-hydroxy-cyclopentyloxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide

The compound of Production Example 38 was obtained as a light yellow oilusing the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methyl esterobtained in Production Example 1,1-(tert-butyldiphenylsiloxy)-2-hydroxycyclopentane and 2-aminothiazole,by the same method as in Production Example 2, a corresponding method,or a combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.62-2.08(6H,m), 3.08(3H,s), 4.24-4.30(1H,m),4.55-4.60(1H,m), 6.87(1H,t,J=2.0 Hz), 7.00(1H,d,J=3.6 Hz),7.14(2H,d,J=8.8 Hz), 7.25(1H,t,J=2.0 Hz), 7.25(1H,d,J=3.6 Hz),7.40(1H,t,J=2.0 Hz), 7.93(2H,d,J=8.8 Hz)

ESI-MS(n/e): 475[M+H]⁺

PRODUCTION EXAMPLE 39

Preparation ofN-(4-acetyl-thiazol-2-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-benzamide

The compound of Production Example 39 was obtained as a white amorphoussubstance using the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methylester obtained in Production Example 1,1-(tert-butyldimethylsiloxy)-2-hydroxypropane and4-acetyl-2-amino-thiazole, by the same method as in Production Example2, a corresponding method, or a combination thereof with an ordinarymethod.

¹HNMR(CDCl₃)δ: 1.32(3H,d,J=6.2 Hz), 2.58(3H,s), 3.10(3H,s),3.80(2H,d,J=5.2 Hz), 4.63(1H,q,J=5.6 Hz), 6.81-6.89(1H,m),7.12-7.19(3H,m), 7.38(1H,br), 7.83(1H,d,J=2.0 Hz), 7.95(2H,dd,J=8.9 Hz)

ESI-MS(m/e): 491[M+H]⁺

PRODUCTION EXAMPLE 40

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methanesulfonylphenoxy)-benzamide

The compound of Production Example 40 was obtained as a white solidusing the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methyl esterobtained in Production Example 1,1-(tert-butyldimethylsiloxy)-2-hydroxypropane and2-amino-4-tert-butyldimethylsiloxymethylthiazole, by the same method asin Production Example 2, a corresponding method, or a combinationthereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.31(3H,d,J=6.2 Hz), 3.09(3H,s), 3.75-3.80(2H,m),4.55-4.66(3H,m), 6.83-6.86(1H,m), 6.88(1H,s), 7.12-7.20(3H,m),7.33-7.36(1H,m), 7.94(2H,d,J=8.6 Hz)

ESI-MS(m/e): 479[M+HM⁺

PRODUCTION EXAMPLE 41

Preparation ofN-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-benzamide

The compound of Production Example 41 was obtained as a light yellow oilusing the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methyl esterobtained in Production Example 1,1-(tert-butyldimethylsiloxy)-2-hydroxypropane and2-amino-4-(1-tertbutyldimethylsiloxy-ethyl)thiazole, by the same methodas in Production Example 2, a corresponding method, or a combinationthereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.31(3H,d,J=6.2 Hz), 1.49(3H,d,J=6.5 Hz), 3.12(3H,s),3.68(2H,d,J=5.0 Hz), 4.60(1H,q,J=6.2 Hz), 4.80-4.90(1H,m), 6.94(1H,s),6.96-6.99(1H,m), 7.23(2H,d,J=8.9 Hz), 7.29-7.32(1H,m), 7.47-7.50(1H,m),7.89(1H,s), 7.96(2H,d,J=8.9 Hz)

ESI-MS(m/e): 493[M+H]⁺

PRODUCTION EXAMPLE 42

Preparation of3-(3-fluoro-4-methanesulfonylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide

After adding 20.4 g (0.68 mol) of 1-bromo-2-fluoro-4-iodobenzene, 20.8 g(0.64 mol) of cesium carbonate and 5.07 g (0.64 mol) of copper (II)oxide to a solution of 9.00 g (0.43 mol) of5-hydroxy-3-methoxymethoxybenzoic acid methyl ester in pyridine (50.0ml), the mixture was stirred at 130° C. for 8 hours under a nitrogenatmosphere. The reaction mixture was filtered and then concentratedunder reduced pressure, acetic acid ethyl ester and saturated aqueousammonium chloride were added to the obtained residue, and the organiclayer was washed with brine, dried and concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (hexane:acetic acid ethyl ester=9:1) to obtain 10.6 g of3-(4-bromo-3-fluoro-phenoxy)-5-methoxymethoxybenzoic acid methyl ester(yield: 65%) as a yellow oil.

After adding 757 mg (7.41 mmol) of sodium methanesulfinate and 1.41 g(7.41 mmol) of copper iodide to a solution of 357 mg (0.93 mmol) of theobtained ester compound in dimethylsulfoxide (6.0 ml), the reactionmixture was stirred at 120° C. for 6 hours. Sodium chloridewater-ammonia water (9:1) was added to the reaction mixture andextraction was performed with acetic acid ethyl ester, and then theorganic layer was washed with brine, dried and concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (hexane:acetic acid ethyl ester=2:1) to obtain 170 mg of3-(3-fluoro-4-methanesulfonyl-phenoxy)-5-methoxymethoxybenzoic acidmethyl ester (yield: 48%) as a colorless oil.

After adding 30.0 ml of trifluoroacetic acid to a solution of 3.34 g(8.69 mmol) of the obtained ester compound in methylene chloride (60.0ml), the reaction mixture was stirred at room temperature for 2 hours.The reaction mixture was concentrated under reduced pressure, and theobtained residue was purified by silica gel column chromatography(hexane:acetic acid ethyl ester=3:7) to obtain 2.59 g of3-(3-fluoro-4-methanesulfonyl-phenoxy)-5-hydroxybenzoic acid methylester (yield: 88%) as a colorless oil.

After adding 87.0 mg (0.46 mmol) of(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and 119 mg (0.46 mmol)of triphenylphosphine to a solution of 77.5 mg (0.23 mmol) of theobtained phenol compound in tetrahydrofuran (1.0 ml), a solution of 0.25ml (0.57 mmol) of diethyl azodicarboxylate in 40% toluene was added, andthe mixture was stirred at room temperature overnight. The reactionmixture was concentrated under reduced pressure, and the obtainedresidue was purified by silica gel column chromatography (hexane:aceticacid ethyl ester=2:1) to obtain 80.0 mg of5-((1S)-2-(t-butyldimethylsiloxy)-1-methyl-ethoxy)-3-(3-fluoro-4-methanesulfonyl-phenoxy)-benzoicacid methyl ester (yield: 69%) as a colorless oil.

The compound of Production Example 42 was obtained as a colorless oilusing the obtained5-((1S)-2-(t-butyldimethylsiloxy)-1-methyl-ethoxy)-3-(3-fluoro-4-methanesulfonyl-phenoxy)-benzoicacid methyl ester and 2-amino-thiazole, by the same method as inProduction Example 2, a corresponding method, or a combination thereofwith an ordinary method.

¹HNMR(CDCl₃)δ: 1.32(3H,d,J=6.3 Hz), 3.23(3H,s), 3.78-3.80(2H,m),4.56-4.61(1H,m), 6.83-6.94(3H,m), 7.01(1H,d,J=3.5 Hz), 7.23(1H,t,J=1.8Hz), 7.37(1H,d,J=3.5 Hz), 7.41(1H,t,J=1.8 Hz), 7.94(1H,t,J=8.2 Hz)

ESI-MS(m/e): 467[M+H]⁺

PRODUCTION EXAMPLE 43

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(5-methyl-thiazol-2-yl)benzamide

The compound of Production Example 43 was obtained as a light yellow oilusing the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methyl esterobtained in Production Example 1,1-(tert-butyldimethylsiloxy)-2-hydroxypropane and2-amino-5-methylthiazole, by the same method as in Production Example 2,a corresponding method, or a combination thereof with an ordinarymethod.

¹HNMR(CDCl₃)δ: 1.29(3H,d,J=6.2 Hz), 2.37(3H,s), 3.08(2H,s),3.69-3.76(2H,m), 4.52-4.57(1H,m), 6.82(1H,t,J=2.0 Hz), 6.88(1H,s),7.12(2H,d,J=8.8 Hz), 7.20(1H,d,J=2.0 Hz), 7.35(1H,d,J=2.0 Hz),7.92(2H,d,J=8.8 Hz)

ESI-MS(m/e): 463[M+H]⁺

PRODUCTION EXAMPLE 44

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-([1,2,4]thiadiazol-5yl)-benzamide

The compound of Production Example 44 was obtained as a light yellow oilusing the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methyl esterobtained in Production Example 1,1-(tert-butyldimethylsiloxy)-2-hydroxypropane and5-amino-1,2,4-thiadiazole, by the same method as in Production Example2, a corresponding method, or a combination thereof with an ordinarymethod.

¹HNMR(CDCl₃)δ: 1.30(3H,d,J=6.2 Hz), 3.12(3H,s), 3.68(2H,d,J=5.1 Hz),4.58-4.85(1H,m), 7.00(1H,s), 7.23(2H,d,J=8.9 Hz), 7.37(1H,s),7.56(1H,s), 7.95(2H,d,J=8.9 Hz), 8.37(1H,s

ESI-MS(m/e): 450[M+H]⁺

PRODUCTION EXAMPLE 45

Preparation ofN-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-benzamide

The compound of Production Example 45 was obtained as a colorlessamorphous substance using the 5-hydroxy-3-(4-methylthiophenoxy)benzoicacid methyl ester obtained in Production Example 1,2-hydroxy-1-methoxypropane and2-amino-4-tertbutyldimethylsiloxymethylthiazole, by the same method asin Production Example 2, a corresponding method, or a combinationthereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.35(3H,d,J=6.3 Hz), 3.09(3H,s), 3.41(3H,s),3.49-3.64(2H,m), 4.58-4.67(3H,m), 6.87-6.92(2H,m), 7.13-7.20(3H,m),7.35-7.38(1H,br), 7.94(2H,d,J=8.8 Hz)

ESI-MS(m/e): 493[M+H]⁺

PRODUCTION EXAMPLE 46

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(5-methoxycarbonyl-pyridin-2-yl)-benzamide

The compound of Production Example 46 was obtained as a white amorphoussubstance using the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methylester obtained in Production Example 1,1-(tert-butyldimethylsiloxy)-2-hydroxypropane and2-amino-5-methoxycarbonyl-pyridine, by the same method as in ProductionExample 2, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 1.34(d,3H,J=6.0 Hz), 3.10(s,3H), 3.80(m,2H), 3.96(s,3H),4.61(m,1H), 6.80(m,1H), 7.16(d,2H,J=8.8 Hz), 7.20(m,1H), 7.37(m,1H),7.94(d,2H,J=8.8 Hz), 8.33-8.46(m,2H), 8.80(br,1H), 8.93(m,1H)

ESI-MS(m/e): 501[M+H]⁺

PRODUCTION EXAMPLE 47

Preparation of6-[5-isopropoxy-3-(4-methanesulfonylphenoxy)-benzoylamino]nicotinic acid

The compound of Production Example 47 was obtained as a white solidusing the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methyl esterobtained in Production Example 1,1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 6-amino-nicotinicacid, by the same method as in Production Example 2, a correspondingmethod, or a combination thereof with an ordinary method.

¹HNMR(DMSO-d₆)δ: 1.29(d,6H,J=6.0 Hz), 3.20(s,3H), 4.76(septet,1H,J=6.0Hz), 6.94(m,1H), 7.23(d,2H,J=8.8 Hz), 7.33(m,1H), 7.49(m,1H),7.94(d,2H,J=8.8 Hz), 8.29(m,2H), 8.87(m,1H), 11.2(s,1H)

ESI-MS(m/e): 471[M+H]⁺

PRODUCTION EXAMPLE 48

Preparation of5-(2-hydroxy-1-methyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide

The compound of Production Example 48 was obtained as a light yellow oilusing the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methyl esterobtained in Production Example 1,2-(tert-butyldimethylsiloxy-3-hydroxy)butane and 2-aminothiazole, by thesame method as in Production Example 2, a corresponding method, or acombination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.25(s,3H,J=6.2 Hz), 1.28(s,3H,J=6.2 Hz), 3.08(s,3H),3.87(m,1H), 4.22(m,1H), 6.85(m,1H), 6.99(m,1H), 7.13(d,2H,J=8.8 Hz),7.23(m,2H), 7.38(m,1H), 7.92(d,2H,J=8.8 Hz), 12.0(br,1H)

ESI-MS(m/e): 463[M+H]⁺

PRODUCTION EXAMPLE 49

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)-3-(4-methanesulfonylphenoxy)-benzamide

The compound of Production Example 49 was obtained as a white amorphoussubstance using the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methylester obtained in Production Example 1,1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 3-aminooxazole, by thesame method as in Production Example 2, a corresponding method, or acombination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.32(d,3H,J=6.0 Hz), 2.04(br,1H), 3.08(s,3H), 3.77(m,2H),4.60(m,1H), 6.87(m,1H), 7.15(d,2H,J=8.8 Hz), 7.19(m,2H), 7.35(m,1H),7.94(d,2H,J=8.8 Hz), 8.30(d,1H,J=1.6 Hz), 9.24(br,1H)

ESI-MS(m/e): 433[M+H]⁺

PRODUCTION EXAMPLE 50

Preparation ofN-(5-hydroxymethyl-thiazol-2-yl)-5-isopropoxy-3-(4-methanesulfonylphenoxy-benzamide

The compound of Production Example 50 was obtained as a light yellow oilusing the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methyl esterobtained in Production Example 1, 2-bromopropane and2-amino-5-formylthiazole, by the same method as in Production Example 1,a corresponding method, or a combination thereof with an ordinarymethod.

¹HNMR(CDCl₃)δ: 1.36(d,6H,J=6.0 Hz), 3.08(s,3H), 4.59(septet,1H,J=6.0Hz), 4.79(s,2H), 6.82(s,1H), 7.14(d,2H,J=8.4 Hz), 7.13-1.18(m,2H),7.31(s,1H), 7.92(d,2H,J=8.4 Hz), 11.2(br,1H)

ESI-MS(m/e): 463[M+H]⁺

PRODUCTION EXAMPLE 51

Preparation ofN-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-benzamide

The-compound of Production Example 51 was obtained as a colorlessamorphous substance using the 5-hydroxy-3-(4-methylthiophenoxy)benzoicacid methyl ester obtained in Production Example 1,1-methoxy-2-hydroxy-propane and2-amino-4-(1-tertbutyldimethylsiloxyethyl)thiazole, by the same methodas in Production Example 2, a corresponding method, or a combinationthereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.35(3H,d,J=6.3 Hz), 1.55(3H,d,J=6.3 Hz), 3.08(3H,s),3.41(3H,s), 3.49-3.64(2H), 4.59-4.70(1H,m), 4.90(1H,q,J=6.3 Hz),6.80(1H,brs), 6.90(1H,br), 7.16(2H,d,J=8.9 Hz), 7.23-7.26(1H,br),7.42(1H,brs), 7.94(2H,d,J=8.9 Hz)

ESI-MS(m/e): 507[M+H]⁺

PRODUCTION EXAMPLE 52

Preparation ofN-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methanesulfonylphenoxy)-5-(tetrahydrofuran-3-yl-oxy)-benzamide

The compound of Production Example 52 was obtained as a colorlessamorphous substance using the 5-hydroxy-3-(4-methylthiophenoxy)benzoicacid methyl ester obtained in Production Example 1,3-hydroxy-tetrahydrofuran and2-amino-4-tertbutyldimethylsiloxymethylthiazole, by the same method asin Production Example 2, a corresponding method, or a combinationthereof with an ordinary method.

¹HNMR(CDCl₃)δ: 2.10-2.36(2H,m), 3.09(3H,s), 3.39-4.07(4H,m), 4.66(2H,s),4.96-5.05(1H,m), 6.84(1H,t,J=2.0 Hz), 7.15-7.20(3H,m), 7.30(1H,br),7.96(2H,d,J=8.8 Hz)

ESI-MS(m/e): 491 [M+H]⁺

PRODUCTION EXAMPLE 53

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(2-methylthiazol-4-yl)-benzamide

The compound of Production Example 53 was obtained as a white amorphoussubstance using the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methylester obtained in Production Example 1,1-(tert-butyldimethylsiloxy)-2-hydroxypropane and4-amino-2-methylthiazole, by the same method as in Production Example 2,a corresponding method, or a combination thereof with an ordinarymethod. ¹HNMR(CDCl₃)δ: 1.32(d,3H,J=6.0 Hz), 2.31(br,1H), 2.66(s,3H),3.09(s,3H), 3.78(m,2H), 4.59(m,1H), 7.13-7.16(m,1H), 7.15(d,2H,J=8.8Hz), 7.32(m,1H), 7.60(s,1H), 7.94(d,2H,J=8.8 Hz), 8.90(br,1H)

ESI-MS(m/e): 463[M+H]⁺

PRODUCTION EXAMPLE 54

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(4-methoxymethyl-thiazol-2-yl)-benzamide

The compound of Production Example 54 was obtained as a white amorphoussubstance using the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methylester obtained in Production Example 1,1-(tert-butyldimethylsiloxy)-2-hydroxypropane and2-amino-4-methoxymethylthiazole, by the same method as in ProductionExample 2, a corresponding method, or a combination thereof with anordinary method. ¹HNMR(CDCl₃)δ: 1.31(d,3H,J=6.0 Hz), 3.09(s,3H),3.42(s,3H), 3.78(m,2H), 4.44(m,2H), 4.57(m,1H), 6.86(m,1H), 6.91(s,1H),7.10-7.26(m,3H), 7.31(m,1H), 7.97(d,2H,J=8.9 Hz), 9.67(br,1H)

ESI-MS(m/e): 493[M+H]⁺

PRODUCTION EXAMPLE 55

Preparation ofN-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-benzamide(diastereoisomer of Production Example 51)

The compound of Production Example 55 was obtained as a colorlessamorphous substance using the 5-hydroxy-3-(4-methylthiophenoxy)benzoicacid methyl ester obtained in Production Example 1,2-hydroxy-1-methoxypropane and2-amino-4-(1-tertbutyldimethylsiloxyethyl)thiazole, by the same methodas in Production Example 2, a corresponding method, or a combinationthereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.35(3H,d,J=6.3 Hz), 1.55(3H,d,J=6.3 Hz), 3.08(3H,s),3.41(3H,s), 3.49-3.64(2H,m), 4.59-4.70(1H,m), 4.90(1H,q,J=6.3 Hz),6.80(1H,brs), 6.90(1H,br), 7.16(2H,d,J=8.9 Hz), 7.23-7.26(1H,br),7.42(1H,brs), 7.94(2H,d,J=8.9 Hz)

ESI-MS(m/e): 507[M+H]⁺

PRODUCTION EXAMPLE 56

Preparation ofN-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-3-(4-methanesulfonylphenoxy)-5-(tetrahydrofuran-3-yl-oxy)-benzamide

The compound of Production Example 56 was obtained as a white solidusing the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methyl esterobtained in Production Example 1, 3-hydroxytetrahydrofuran and2-amino-4-(1-tertbutyldimethylsiloxyethyl)thiazole, by the same methodas in Production Example 2, a corresponding method, or a combinationthereof with an ordinary method.

¹HNMR(CDCl₃)δ: 2.10-2.36(2H,m), 0.39(3H,s), 3.89-4.07(4H,m),4.85-4.95(1H,m), 4.97-5.04(1H,m), 6.81-6.85(2H,m), 7.16(2H,d,J=8.7 Hz),7.23(1H,brs), 7.34(1H,brs), 7.96(2H,d,J=8.7 Hz)

ESI-MS(m/e): 505[M+H]⁺

PRODUCTION EXAMPLE 57

Preparation ofN-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-3-(4-methanesulfonylphenoxy)-5-(tetrahydrofuran-3-yl-oxy)-benzamide(diastereoisomer of Production Example 56)

The compound of Production Example 57 was obtained as a white solid, bythe same method as in Production Example 56, a corresponding method, ora combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 2.10-2.35(2H,m), 3.09(3H,s), 3.89-4.06(4H,m),4.86-4.95(1H,m), 4.97-5.05(1H,m), 6.81-6.85(2H,m), 7.16(2H,d,J=8.7 Hz),7.22(1H,brs), 7.34(1H,brs), 7.96(2H,d,J=8.7 Hz)

ESI-MS(m/e): 505[M+H]⁺

PRODUCTION EXAMPLE 58

Preparation ofN-(2,5-dimethylthiazol-4-yl)-5-2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-benzamide

The compound of Production Example 58 was obtained as a light yellow oilusing the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methyl esterobtained in Production Example 1,1-(tert-butyldimethylsiloxy)-2-hydroxypropane and4-amino-2,5-dimethylthiazole, by the same method as in ProductionExample 2, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 1.28(d,3H,J=6.0 Hz), 2.32(s,3H), 2.56(s,3H), 3.07(s,3H),3.72(m,2H), 4.53(m,1H) 6.79(t,1H,J=2.0 Hz ), 7.08(dd,2H,J=2.0,6.8 Hz),7.18(s,1H), 7.32(s,1H), 7.89(dd,2H,J=2.0,6.8 Hz), 8.67(br,1H)

ESI-MS(m/e): 477[M+H]⁺

PRODUCTION EXAMPLE 59

Preparation of5-isopropoxy-3-(4-methoxycarbonylaminomethylphenoxy)-N-thiazol-2-yl-benzamide

After adding 41.0 g (0.30 mmol) of potassium carbonate and 23.8 g (0.19mmol) of 2-bromopropane to a solution of 25.0 g (0.15 mol) of3,5-dihydroxybenzoic acid methyl ester in N,N-dimethylformamide (250ml), the reaction mixture was stirred at 80° C. for 4 hours. Water wasadded to the reaction mixture, extraction was performed with acetic acidethyl ester, and then the organic layer was washed with brine, dried andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (hexane:acetic acid ethyl ester=5:1)to obtain 12.0 g of 5-hydroxy-3-isopropoxybenzoic acid methyl ester(yield: 38%) as a colorless oil.

After adding 1.05 g of molecular sieves 4 A, 1.00 g (6.70 mol) ofp-formylphenylboric acid, 605 mg (3.30 mol) of copper (II) acetate and2.32 ml (16.6 mol) of triethylamine to a solution of 700 mg (3.30 mmol)of the obtained phenol compound in methylene chloride (30 ml), themixture was stirred at room temperature overnight under a oxygenatmosphere. The reaction mixture was filtered and then concentratedunder reduced pressure, and the obtained residue was purified by silicagel column chromatography (hexane:acetic acid ethyl ester=5:1) to obtain593 mg of 3-(4-formylphenoxy)-5-isopropoxybenzoic acid methyl ester(yield: 57%) as a colorless oil.

After adding 85.0 mg (2.25 mmol) of sodium borohydride to a solution of590 mg (1.88 mmol) of the obtained formyl compound in methanol (20 ml),the reaction mixture was stirred at room temperature for 16 hours. Thereaction mixture was concentrated, and then saturated aqueous sodiumhydrogencarbonate was added, extraction was performed with chloroform,and the organic layer was dried and concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography(hexane:acetic acid ethyl ester=2:1) to obtain 567 mg of3-(4-hydroxymethylphenoxy)-5-isopropoxybenzoic acid methyl ester (yield:95%) as a colorless oil.

After adding 0.18 ml (1.26 mmol) of triethylamine and 0.073 ml (0.95mmol) of methanesulfonyl chloride to a solution of 200 mg (0.63 mmol) ofthe obtained alcohol compound in chloroform (10 ml), the reactionmixture was stirred at 50° C. for 15 minutes. Saturated aqueous sodiumhydrogencarbonate was added to the reaction mixture, extraction wasperformed with chloroform, and the organic layer was dried and thenconcentrated under reduced pressure. After adding 5.0 ml of DMF to theobtained residue and dissolving it therein, 123 mg (1.90 mmol) of sodiumazide was added and the mixture was stirred at 80° C. for 1 hour. Waterwas added to the reaction mixture, extraction was performed with aceticacid ethyl ester, and the organic layer was dried and then concentratedunder reduced pressure to obtain a crude azide compound.

After adding 247 mg (1.26 mmol) of triphenylphosphine to a solution of11 ml of the obtained azide compound in tetrahydrofuran-water (10:1),the reaction mixture was stirred at 90° C. for 14 hours. A 2N aqueoushydrochloric acid solution was added to the reaction mixture to producean acidic aqueous solution. The mixture was washed with acetic acidethyl ester, and then a 4N aqueous sodium hydroxide solution was addedto the aqueous layer to produce a basic aqueous solution, after whichextraction was performed with chloroform and the organic layer was driedand concentrated under reduced pressure to obtain 67.8 mg of a crudeamine compound (yield: 34%).

After adding 0.057 ml (0.41 mmol) of triethylamine and 0.024 ml (0.31mmol) of chloroformic acid methyl ester to a solution of the obtainedamine compound in chloroform (5.0 ml), the mixture was stirred at roomtemperature for 1 hour. Saturated aqueous sodium hydrogencarbonate wasadded to the reaction mixture, and then extraction was performed withchloroform and the organic layer was dried and concentrated underreduced pressure to obtain a crude methoxycarbonylaminomethyl compound.

After adding 1.0 ml (4.00 mmol) of a 4N aqueous sodium hydroxidesolution to a 5:3 solution of the obtained methoxycarbonylaminomethylcompound in tetrahydrofuran-methanol (8.0 ml), the reaction mixture wasstirred at 50° C. overnight. Saturated aqueous ammonium chloride wasadded to the reaction mixture, extraction was performed with chloroform,the organic layer was dried and then concentrated under reducedpressure, and the obtained residue was purified by silica gel columnchromatography (chloroform:methanol=30:1) to obtain 63.1 mg of5-isopropoxy-3-(4-methoxycarbonylaminomethylphenoxy)-benzoic acid(yield: 85%) as a white solid.

After adding 33.0 mg (0.33 mol) of 2-aminothiazole, 76.0 mg (0.49 mmol)of 1-hydroxybenzotriazole hydrate and 63.0 mg (0.33 mol) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to asolution of the obtained carboxyl compound in N,N-dimethylformamide (3.0ml), the mixture was stirred at room temperature overnight. Water wasadded to the reaction mixture, extraction was performed with acetic acidethyl ester, the reaction mixture was concentrated under reducedpressure, and the obtained residue was purified by silica gel columnchromatography (chloroform:methanol=100:1) to obtain the title compoundas a white solid. The analysis data for the compound obtained inProduction Example 59 are shown below.

¹HNMR(CDCl₃)δ: 1.34(6H,d,J=6.0 Hz), 3.71(3H,s), 4.36(2H,d,J=5.5 Hz),4.57(1H,m), 4.99-5.10(1H,br), 6.75(1H,brs), 6.96-7.05(4H,m),7.20(1H,br), 7.27-7.34(3H,m), 10.70-10.88(1H,br)

ESI-MS(m/e): 442[M+H]⁺

Compounds for Production Examples 60 to 64 were obtained by the samemethod as in Production Example 59 above. The structures and analysisdata for these compounds are shown below.

PRODUCTION EXAMPLE 60

Preparation of5-isopropoxy-3-(4-methylcarbamoyl-phenoxy)-N-thiazol-2-yl-benzamide

The compound of Production Example 60 was obtained as a colorlessamorphous substance using 2-aminothiazole and3-(4-methylcarbamoyl-phenoxy)-5-isopropoxybenzoic acid methyl esterobtained by condensation reaction between methylamine and3-(4-carboxyphenoxy)-5-isopropoxybenzoic acid methyl ester obtained byoxidizing the formyl group of the3-(4-formylphenoxy)-5-isopropoxybenzoic acid methyl ester obtained inProduction Example 59, by the same method as in Production Example 2, acorresponding method, or by a similar method.

¹HNMR(CDCl₃)δ: 1.36(6H,d,J=6.1 Hz), 3.00(3H,d,J=4.8 Hz), 4.58(1H,m),6.12-6.21(1H,br), 6.79(1H,t,J=2.2 Hz), 6.99-7.06(4H,m), 7.24-7.27(1H,m),7.34(1H,d,J=3.6 Hz), 7.72(2H,m)

ESI-MS(m/e): 412[M+H]⁺

PRODUCTION EXAMPLE 61

Preparation of3-(4-dimethylcarbamoyl-phenoxy)-5-isopropoxy-N-thiazol-2-yl-benzamide

The compound of Production Example 61 was obtained as a colorlessamorphous substance using the 3-(4-carboxylphenoxy)-5-isopropoxybenzoicacid methyl ester obtained in Production Example 60, dimethylamine and2-aminothiazole, by the same method as in Production Example 60, acorresponding method, or a similar method.

¹HNMR(CDCl₃)δ: 1.34(6H,d,J=6.0 Hz), 2.98-3.15(6H,br), 4.56(1H,m),6.78(1H,t,J=2.3 Hz), 6.98(1H,d,J=3.6 Hz), 7.00-7.06(2H,m),7.14-7.17(1H,m), 7.24-7.28(2H,m), 7.40-7.47(2H,m)

ESI-MS(m/e): 426[M+H]⁺

PRODUCTION EXAMPLE 62

Preparation of5-isopropoxy-3-(4-methylcarbonylaminomethyl-phenoxy)-N-thiazol-2-yl-benzamide

The compound of Production Example 62 was obtained as a colorlessamorphous substance using the3-(4-aminomethylphenoxy)-5-isopropoxybenzoic acid methyl ester obtainedin Production Example 59, acetyl chloride and 2-aminothiazole, by thesame method as in Production Example 59, a corresponding method, or acombination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.35(6H,d,J=6.0 Hz), 2.05(3H,s), 4.40(2H,d,J=5.6 Hz),4.57(1H,m), 5.95-6.07(1H,br), 6.78(1H,t,J=2.2 Hz), 6.93-7.02(4H,m),7.20-7.32(4H,m)

ESI-MS(m/e): 426[M+H]⁺

PRODUCTION EXAMPLE 63

Preparation of5-isopropoxy-3-(4-methanesulfonylaminomethyl-phenoxy)-N-thiazol-2-yl-benzamide

The compound of Production Example 63 was obtained as a colorlessamorphous substance using the3-(4-aminomethylphenoxy)-5-isopropoxybenzoic acid methyl ester obtainedin Production Example 59, methanesulfonyl chloride and 2-aminothiazole,by the same method as in Production Example 59, a corresponding method,or a combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.36(6H,d,J=6.0 Hz), 2.94(3H,s), 4.32(2H,d,J=6.1 Hz),4.60(1H,m), 4.79-4.88(1H,m), 6.77(1H,m), 6.98-7.38(8H,m)

ESI-MS(m/e): 462[M+H]⁺

PRODUCTION EXAMPLE 64

Preparation of3-[4-(1-hydroxy-propyl)-phenoxy]-5-isopropoxy-N-thiazol-2-yl-benzamide

The compound of Production Example 64 was obtained as a colorlessamorphous substance using the 3-(4-formylphenoxy)-5-isopropoxybenzoicacid methyl ester obtained in Production Example 59, ethylmagnesiumbromide and 2-aminothiazole, by the same method as in Production Example59, a corresponding method, or a combination thereof with an ordinarymethod.

The reaction between the 3-(4-formylphenoxy)-5-isopropoxybenzoic acidmethyl ester and ethylmagnesium bromide is a Grignard reaction, and itmay be conducted by a method described in the relevant literature (forexample, Comprehensive Organic Transformations, Richard L. et al., VCHPublishers, 1988), a corresponding method, or a combination thereof withan ordinary method.

¹HNMR(CDCl₃)δ: 0.92(3H,t,J=7.4 Hz), 1.34(6H,d,J=6.1 Hz),1.67-1.88(2H,m), 4.51-4.63(2H,m), 6.76(1H,t,J=2.3 Hz), 6.95-7.07(3H,m),7.04-7.07(1H,m), 7.20-7.24(2H,m), 7.32(2H,d,J=8.5 Hz)

ESI-MS(m/e): 413[M+H]⁺

PRODUCTION EXAMPLE 65

Preparation of6-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl)-phenoxy]-nicotinic acid methylester

After adding 10 ml of 4N aqueous sodium hydroxide solution to a solutionof the 3.0 g (14.3 mmol) of 5-hydroxy-3-isopropoxybenzoic acid methylester obtained in Production Example 59 in methanol (50 ml), the mixturewas stirred at room temperature for 12 hours. The reaction mixture wasconcentrated under reduced pressure, and then saturated aqueous ammoniumchloride was added, extraction was performed with chloroform, and theorganic layer was dried and then concentrated under reduced pressure.The obtained residue was purified by silica gel chromatography(chloroform:methanol=50:1) to obtain 2.44 g of5-hydroxy-3-isopropoxybenzoic acid (yield: 87%) as a white solid.

After adding 2.45 g (24.5 mmol) of 2-aminothiazole, 3.40 ml (24.5 mmol)of triethylamine and 4.14 g (24.5 mmol) of2-chloro-1,3-dimethylimidazolinium chloride to a solution of 2.40 g(12.2 mmol) of the obtained carboxylic acid in chloroform (50 ml) whilecooling on ice, the mixture was stirred at room temperature for 13hours. Saturated aqueous ammonium chloride was added to the reactionmixture, extraction was performed with chloroform, and the organic layerwas dried and then concentrated under reduced pressure. After adding 10ml of 4N aqueous sodium hydroxide to a solution of the obtained residuein methanol (40 ml), the mixture was stirred at room temperature for 1hour. The reaction mixture was concentrated under reduced pressure, andthen saturated aqueous ammonium chloride was added, extraction wasperformed with chloroform, and the organic layer was dried and thenconcentrated under reduced pressure. The obtained residue was purifiedby silica gel chromatography (chloroform:methanol=100:1) to obtain 1.81g of 5-hydroxy-3-isopropoxy-N-thiazol-2-yl-benzamide (yield: 53%) as awhite solid.

After adding 123 mg (0.72 mmol) of 6-chloronicotinic acid methyl esterand 199 mg (1.44 mmol) of potassium carbonate to a solution of 100 mg(0.36 mmol) of the obtained amide compound in N,N-dimethylformamide(10.0 ml), the mixture was stirred at 80° C. for 18 hours under anitrogen atmosphere. Water was added to the reaction mixture, extractionwas performed with ethyl acetate, and the organic layer was dried andthen concentrated under reduced pressure. The obtained residue waspurified by silica gel chromatography (hexane:ethyl acetate=3:1) toobtain the title compound as a white solid. The analysis data for thecompound obtained in Production Example 65 are shown below.

¹HNMR(CDCl₃)δ: 1.36(6H,d,J=6.0 Hz), 3.93(3H,s), 4.60(1H,m),6.91-7.02(3H,m), 7.29-7.40(3H,m), 8.31(1H,dd,J=8.6,2.4 Hz),8.81(1H,d,J=2.4 Hz)

ESI-MS(m/e): 414[M+H]⁺

PRODUCTION EXAMPLE 66

Preparation of3-(5-hydroxymethyl-pyridin-2-yl-oxy)-5-isopropoxy-N-thiazol-2-yl-benzamide

After adding 6.0 mg (0.16 mmol) of lithium aluminum hydride to asolution of 60.0 mg (0.15 mmol) of the6-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl)-phenoxy]-nicotinic acid methylester obtained in Production Example 65 in tetrahydrofuran (5.0 ml)while cooling on ice, the mixture was stirred at 0° C. for 1 hour.Saturated aqueous sodium hydrogencarbonate was added to the reactionmixture, extraction was performed with ethyl acetate, and the organiclayer was dried and then concentrated under reduced pressure. Theobtained residue was purified by silica gel chromatography(chloroform:methanol=30:1) to obtain the title compound as a whitesolid. The analysis data for the compound obtained in Production Example66 are shown below.

¹HNMR(CDCl₃)δ: 1.36(6H,d,J=6.0 Hz), 4.54-4.64(1H,m), 4.68(2H,s),6.90(1H,t,J=2.1 Hz), 6.92-6.98(2H,m), 7.22(1H,t,J=1.7 Hz),7.31-7.37(2H,m), 7.77(1H,dd,J=2.8,8.3 Hz), 8.14(1H,br)

ESI-MS(m/e): 386[M+H]⁺

Compounds for Production Examples 67 to 73 were obtained by the samemethod as in Production Example 65 or 66 above. The analysis data forthese compounds are shown below. 20 Production Example 67

Preparation of5-isopropoxy-3-(5-methanesulfonylpyridin-2-yl)-N-thiazol-2-yl-benzamide

The compound of Production Example 67 was obtained as a light yellow oilusing the 5-hydroxy-3-isopropoxy-N-thiazol-2-yl-benzamide obtained inProduction Example 65 and 2,5-bismethanesulfonylpyridine, by the samemethod as in Production Example 65, a corresponding method, or acombination thereof with an ordinary method.

The 2,5-bismethanesulfonylpyridine was obtained by reacting2,5-dibromopyridine with sodium thiomethoxide to obtain2,5-bis-methylthiopyridine, and then oxidizing it withmetachloroperbenzoic acid. The reaction between 2,5-dibromopyridine andsodium methoxide and the oxidation of 2,5-bis-methylthiopyridine withmetachloroperbenzoic acid may be carried out according to ordinarymethods.

¹HNMR(CDCl₃)δ: 1.37(6H,d,J=6.1 Hz), 3.11(3H,s), 4.58-4.66(1H,m),6.93(1H,t,J=1.8 Hz), 6.99(1H,d,J=3.6 Hz), 7.12(1H,d,J=8.7 Hz),7.29(1H,d,J=1.8 Hz), 7.36(1H,d,J=3.6 Hz), 7.40(1H,d,J=1.8 Hz),8.21(1H,dd,J=2.6,8.7 Hz), 8.71 (1H,d,J=2.6 Hz)

ESI-MS(m/e): 434[M+H]⁺

PRODUCTION EXAMPLE 68

Preparation of3-(5-acetyl-pyridin-2-yl-oxy)-5-isopropoxy-N-thiazol-2-yl-benzamide

The compound of Production Example 68 was obtained as a white solidusing 5-hydroxy-3-isopropoxy-N-thiazol-2-yl-benzamide obtained in thesame manner as Production Example 65 and 2-chloro-5-acetylpyridine, bythe same method as in Production Example 65, a corresponding method, ora combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.37(6H,d,J=6.0 Hz), 2.59(3H,s), 4.61(1H,m),6.93(1H,t,J=2.1 Hz), 6.98(1H,d,J=3.6 Hz), 7.04(1H,d,J=8.6 Hz),7.29(1H,t,J=2.1 Hz), 7.38(2H,m), 8.30(1H,dd,J=2.5,8.6 Hz),8.75(1H,d,J=2.5 Hz)

ESI-MS(m/e): 398[M+H]⁺

PRODUCTION EXAMPLE 69

Preparation of5-isopropoxy-3-(5-methoxycarbonyl-pyrazin-2-yl-oxy)-N-thiazol-2-yl-benzamide

The compound of Production Example 69 was obtained as a colorlessamorphous substance using5-hydroxy-3-isopropoxy-N-thiazol-2-yl-benzamide obtained in the samemanner as Production Example 65 and 2-chloro-5-methoxycarbonylpyrazine,by the same method as in Production Example 65, a corresponding method,or a combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.38(6H,d,J=6.0 Hz), 4.03(3H,s), 4.57-4.65(1H,m),6.95(1H,t,J=2.1 Hz), 7.00(1H,d,J=3.6 Hz), 7.33-7.35(1H,m),7.37-7.42(2H,m), 8.54(1H,d,J=1.2 Hz), 8.85(1H,d,J=1.2 Hz)

ESI-MS(m/e): 415[M+H]⁺

PRODUCTION EXAMPLE 70

Preparation of3-(5-cyano-pyridin-2-yl-oxy)-5-isopropoxy-N-thiazol-2-yl-benzamide

The compound of Production Example 70 was obtained as a colorlessamorphous substance using5-hydroxy-3-isopropoxy-N-thiazol-2-yl-benzamide obtained in the samemanner as Production Example 65 and 2,5-dibromopyridine, by reactionbetween3-(5-bromo-pyridin-2-yl-oxy)-5-isopropoxy-N-thiazol-2-yl-benzamideobtained in the same manner as Production Example 65 and copper (I)cyanide.

The reaction between3-(5-bromo-pyridin-2-yl-oxy)-5-isopropyl-N-thiazol-2-yl-benzamide andcopper cyanide may be carried out by a method described in the relevantliterature (for example, Comprehensive Organic Transformations, RichardL. et al., VCH Publishers, 1988), a corresponding method, or acombination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.37(6H,d,J=6.1 Hz), 4.61(1H,m), 6.89-6.92(1H,m),6.97-7.01(1H,m), 7.06-7.09(1H,m), 7.26-7.29(1H,m), 7.35-7.40(1H,m),7.93-7.98(1H,m), 8.47-8.49(1H,m)

ESI-MS(m/e): 381 [M+H]⁺

PRODUCTION EXAMPLE 71

Preparation of5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridin-4-yl-oxy)-N-thiazol-2-yl-benzamide

The compound of Production Example 71 was obtained as a white solidusing 5-hydroxy-3-isopropoxybenzoic acid methyl ester obtained in thesame manner as Production Example 59, 4-bromo-pyridine hydrochloride and2-aminothiazole, by the same method as in Production Example 65, acorresponding method, or a combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.31(6H,d,J=6.0 Hz), 4.73-4.83(1H,m), 5.5 1(1H,d,J=2.6Hz), 6.03(1H,dd,J=2.5,7.4 Hz), 6.99(1H,t,J=2.2 Hz), 7.30(1H,d,J=3.6 Hz),7.38-7.44(2H,m), 7.55-7.59(2H,m)

ESI-MS(m/e): 372[M+H]⁺

PRODUCTION EXAMPLE 72

Preparation of5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridin-3-yl-oxy)-N-thiazol-2-yl-benzamide

The compound of Production Example 72 was obtained as white crystalsusing 5-hydroxy-3-isopropoxybenzoic acid methyl ester obtained in thesame manner as Production Example 59, 3-bromo-2-hydroxy-pyridine and2-aminothiazole, by the same method as in Production Example 65, acorresponding method, or a combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.34(6H,d,J=6.0 Hz), 4.62-4.72(1H,m),6.41(1H,dd,J=6.7,7.2 Hz), 6.76(1H,t,J=2.3 Hz), 7.10-7.13(1H,dd,J=1.5,2.2Hz), 7.14(1H,d,J=3.6 Hz), 7.27-7.29(1H,m), 7.30-7.37(2H,m),7.48(2H,d,J=3.6 Hz)

ESI-MS(m/e): 372[M+H]⁺

PRODUCTION EXAMPLE 73

Preparation of5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridin-3-yl-oxy)-N-thiazolo[5,4-b]pyridin-2-yl-benzamide

The compound of Production Example 73 was obtained as a white solidusing 5-hydroxy-3-isopropoxybenzoic acid methyl ester obtained in thesame manner as Production Example 59, 3-bromo-2-hydroxy-pyridine and2-amino-thiazolo[5,4-b]pyridine, by the same method as in ProductionExample 65, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 1.31(6H,d,J=6.0 Hz), 4.68-4.81(1H,m), 6.25(1H,t,J=6.9Hz), 6.68-6.72(1H,m), 7.13-7.16(1H,m), 7.31-7.40(2H,m), 7.44-7.54(2H,m),8.12(1H,d,J=7.8 Hz), 8.46-8.52(1H,m)

ESI-MS(m/e): 423[M+H]⁺

PRODUCTION EXAMPLE 74

Preparation of5-isopropoxy-3-([1,3,4]thiadiazol-2-ylsulfanyl)-N-thiazolo[5,4-b]-pyridine-2-yl-benzamide

After adding 298 mg (2.16 mmol) of potassium carbonate and 0.12 ml (1.29mmol) of 2-bromopropane to a solution of 120 mg (0.43 mol) of3-hydroxy-5-iodobenzoic acid methyl ester in N,N-dimethylformamide (4.0ml), the reaction mixture was stirred at 80° C. overnight. Water wasadded to the reaction mixture, extraction was performed with acetic acidethyl ester, and then the organic layer was washed with brine, dried andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (hexane:acetic acid ethyl ester=5:1)to obtain 133 mg of 5-iodo-3-isopropoxybenzoic acid methyl ester (yield:96%) as a colorless oil.

After adding 292 mg (2.47 mol) of 2-mercapto-1,3,4-thiadiazole, 456 mg(3.30 mol) of potassium carbonate, 27.0 mg (0.25 mmol) of hydroquinoneand 35.0 mg (0.25 mmol) of copper (I) bromide to a solution of 132 mg(0.41 mmol) of the obtained iodo compound in N,N-dimethylformamide (10ml), the mixture was stirred at 130° C. for 40 minutes under a nitrogenatmosphere. Water was added to the reaction mixture, extraction wasperformed with acetic acid ethyl ester, and then the organic layer waswashed with brine, dried and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(hexane:acetic acid ethyl ester=1:1) to obtain 8.90 mg of5-isopropoxy-3-(1,3,4-thiadiazol-2-yl-thio)benzoic acid methyl ester(yield: 7%) as a colorless oil.

After adding 0.14 ml (0.29 mmol) of a 2N aqueous sodium hydroxidesolution to a solution of the obtained ester compound in methanol (1.0ml), the reaction mixture was stirred at room temperature for 5 hours. A2N aqueous hydrochloric acid solution was added to the reaction mixture,extraction was performed with acetic acid ethyl ester, and then theorganic layer was washed with brine, dried and concentrated underreduced pressure to obtain a crude carboxyl compound.

After adding 8.20 mg (0.054 mol) of 2-amino-thiazolo[5,4-b]-pyridine,5.00 mg (0.037 mmol) of 1-hydroxybenzotriazole hydrate and 7.10 mg(0.037 mol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride to a solution of the obtained carboxyl compound inN,N-dimethylformamide (1.2 ml), the mixture was stirred at roomtemperature overnight. The reaction mixture was concentrated underreduced pressure, and the obtained residue was purified by silica gelcolumn chromatography (hexane:acetic acid ethyl ester=1:1) to obtain thetitle compound as a white solid. The analysis data for the compoundobtained in Production Example 74 are shown below.

¹HNMR(CDCl₃)δ: 1.32(6H,d,J=6.0 Hz), 4.54-4.62(1H,m),7.32(1H,dd,J=4.6,8.2 Hz), 7.37(1H,t,J=1.8 Hz), 7.56(1H,t,J=1.8 Hz),7.74(1H,dd,J=1.4,8.2 Hz), 7.79(1H,t,J=1.8 Hz), 8.52(1H,dd,J=1.4,4.6 Hz),9.07(1H,s)

ESI-MS(m/e): 430[M+H]⁺

Compounds for Production Example 75 to Production Example 88 wereobtained by the same method as in Production Example 74 above. Theanalysis data for representative compounds among these are shown below.

PRODUCTION EXAMPLE 75

Preparation of5-isopropoxy-3-(4-methyl-[1,2,4]triazol-3-ylsulfanyl)-N-thiazol-2-yl-benzamide

The compound of Production Example 75 was obtained as a colorlessamorphous substance using the 5-iodo-3-isopropoxybenzoic acid methylester obtained in Production Example 74, 2-aminothiazole and3-mercapto-4-methyl-[1,2,4]triazole, by the same method as in ProductionExample 74, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 1.31(6H,d,J=5.9 Hz), 3.65(3H,s), 4.53-4.57(1H,m),6.98(1H,q,J=3.5 Hz), 7.06(1H,s) 7.20(1H,d,J=3.5 Hz), 7.41(1H,s),7.53(1H,s), 8.29(1H,s)

ESI-MS(m/e): 374[M−H]⁻

PRODUCTION EXAMPLE 76

Preparation of5-isopropoxy-3-thiazol-2-ylsulfanyl-N-thiazol-2-yl-benzamide

The compound of Production Example 76 was obtained as a colorlessamorphous substance using the 5-iodo-3-isopropoxybenzoic acid methylester obtained in Production Example 75, 2-aminothiazole and2-mercapto-thiazole, by the same method as in Production Example 74, acorresponding method, or a combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.33(6H,d,J=6.0 Hz), 4.54-4.62(1H,m), 6.95(1H,d,J=3.6Hz), 7.15(1H,d,J=3.6 Hz), 7.29-7.32(2H,m), 7.50(1H,dd,J=1.5,2.2 Hz),7.69(1H,d,J=1.5 Hz), 7.77(1H,d,J=3.4 Hz)

PRODUCTION EXAMPLE 77

Preparation of5-isopropoxy-3-(4H-[1,2,4]triazol-3-ylsulfanyl)-N-thiazol-2-yl-benzamide

The compound of Production Example 77 was obtained as a colorlessamorphous substance using the 5-iodo-3-isopropoxybenzoic acid methylester obtained in Production Example 74, 2-aminothiazole and3-mercapto-[1,2,4]triazole, by the same method as in Production Example74, a corresponding method, or a combination thereof with an ordinarymethod.

¹HNMR(CDCl₃)δ: 1.34(6H,d,J=6.0 Hz), 4.59-4.63(1H,m), 7.04(1H,d,J=2.5Hz), 7.44(1H,dd,J=1.0 Hz), 7.49(1H,t,J=1.0 Hz), 7.49(1H,d,J=2.5 Hz),7.67(1H,t,J=1.0 Hz), 8.24(1H,s)

ESI-MS(m/e): 362[M+H]⁺

PRODUCTION EXAMPLE 78

Preparation of5-isopropoxy-3-([1,3,4]thiadiazol-2-ylsulfanyl)-N-thiazol-2-yl-benzamide

The compound of Production Example 78 was obtained as a colorlessamorphous substance using the 5-iodo-3-isopropoxybenzoic acid methylester obtained in Production Example 74, 2-aminothiazole and2-mercapto-[1,3,4]thiadiazole, by the same method as in ProductionExample 74, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CH₃OD)δ: 1.37(6H,d,J=6.0 Hz), 4.71-4.81(1H,m), 7.14(1H,d,J=3.7Hz), 7.45(1H,t,J=1.8 Hz), 7.50(1H,d,J=3.7 Hz), 7.68(1H,t,J=1.8 Hz),7.89(1H,t,J=1.8 Hz), 9.32(1H,s)

ESI-MS(m/e): 379[M+H]⁺

PRODUCTION EXAMPLE 79

Preparation of5-isopropoxy-3-(5-methylsulfanyl-[1,3,4]thiadiazol-2-ylsulfanyl)-N-thiazol-2-yl-benzamide

The compound of Production Example 79 was obtained as a colorless oilusing the 5-iodo-3-isopropoxybenzoic acid methyl ester obtained inProduction Example 74, 2-aminothiazole and2-mercapto-5-methylsulfanyl-[1,3,4]thiadiazole, by the same method as inProduction Example 74, a corresponding method, or a combination thereofwith an ordinary method.

¹HNMR(CDCl₃)δ: 1.34(6H,d,J=6.0 Hz), 2.75(3H,s), 4.55-4.63(1H,m),6.97(1H,d,J=3.6 Hz), 7.13(1H,d,J=3.6 Hz), 7.32(1H,t,J=1.8 Hz),7.53(1H,t,J=1.8 Hz), 7.72(1H,t,J=1.8 Hz)

ESI-MS(m/e): 425[M+H]⁺

PRODUCTION EXAMPLE 80

Preparation of5-isopropoxy-3-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanyl)-N-thiazol-2-yl-benzamide

The compound of Production Example 80 was obtained as a colorlessamorphous substance using the 5-iodo-3-isopropoxybenzoic acid methylester obtained in Production Example 74, 2-aminothiazole and2-mercapto-5-methyl-[1,3,4]thiadiazole, by the same method as inProduction Example 74, a corresponding method, or a combination thereofwith an ordinary method.

¹HNMR(CDCl₃)δ: 1.35(6H,d,J=6.0 Hz), 2.72(3H,s), 4.56-4.64(1H,m),6.97(1H,d,J=3.6 Hz), 7.17(1H,d,J=3.6 Hz), 7.35(1H,t,J=1.8 Hz),7.54(1H,t,J=1.8 Hz), 7.73(1H,J=1.8 Hz)

ESI-MS(m/e): 393[M+H]⁺

PRODUCTION EXAMPLE 81

Preparation of5-(tetrahydrofuran-3-yl-oxy)-N-thiazol-2-yl-3-(4H-[1,2,4]triazol-3-ylsulfanyl)-benzamide

The compound of Production Example 81 was obtained as a colorless oil bythe same method as in Production Example 74, a corresponding method, ora combination thereof with an ordinary method, using (3R)-3-bromopropaneinstead of 2-bromopropane, and using5-iodo-3-(tetrahydrofuran-3-yloxy)be acid methyl ester produced by thesame method as in Production Example 74, 2-aminothiazole and3-mercapto-[1,2,4]triazole.

¹HNMR(CDCl₃)δ: 2.05-2.24(2H,m), 3.89-4.02(4H,m), 4.94-4.98(1H,m),7.06(1H,d,J=3.6 Hz), 7.23(1H,t,J=1.8 Hz), 7.40(1H,d,J=1.8 Hz),7.48(1H,d,J=3.6 Hz), 7.68(1H,d,J=1.8 Hz), 8.32(1H,s)

ESI-MS(m/e): 390[M+H]⁺

PRODUCTION EXAMPLE 82

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-N-(4-methyl-thiazol-2-yl)-3-([1,3,4]thiadiazol-2-ylsulfanyl)-benzamide

The compound of Production Example 82 was obtained as a colorless oilusing 3-hydroxy-5-iodo-benzoic acid methyl ester,1-tert-dimethylsiloxy-2-hydroxypropane and 2-amino-4-methyl-thiazole,and using3-(2-tert-butyl-dimethylsiloxy-1-methyl-ethoxy)-5-iodo-N-(4-methyl-thiazol-2-yl)-benzamideobtained in the same manner as Production Example 65 and2-mercapto-[1,3,4]thiadiazole, by the same method as in ProductionExample 74, a corresponding method, or a combination thereof with anordinary method. Removal of the tert-butyldimethylsiloxy group servingas the protective group for the hydroxy group may be accomplished by thesame method as in Production Example 2, a corresponding method, or acombination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.32(d,3H,J=6.2 Hz), 2.38(s,3H), 4.79(m,2H), 4.65(m,1H),6.63(s,1H), 7.38(m,1H), 7.72(m,1H), 7.82(m,1H), 9.08(s,1H)

ESI-MS(m/e): 409[M+H]⁺

PRODUCTION EXAMPLE 83

Preparation of5-(3-hydroxy-1-methyl-propoxy)-N-(4-methyl-thiazol-2-yl)-3-([1,3,4]thiadiazol-2-ylsulfanyl)-benzamide

The compound of Production Example 83 was obtained as a white amorphoussubstance using 3-hydroxy-5-iodo-benzoic acid methyl ester,5-tert-butyldimethylsiloxy-pentan-2-ol and 2-amino-4-methyl-thiazole,and using3-(3-tert-butyldimethylsiloxy-1-methyl-propoxy)-5-iodo-N-(4-methyl-thiazol-2-yl)-benzamideobtained in the same manner as Production Example 65 and2-mercapto-[1,3,4]thiadiazole, by the same method as in ProductionExample 74, a corresponding method, or a combination thereof with anordinary method. Removal of the tert-butyldimethylsiloxy group servingas the protective group for the hydroxy group may be accomplished by thesame method as in Production Example 2, a corresponding method, or acombination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.33(d,3H,J=6.1 Hz), 2.10-1.75(m,4H), 2.18(d,1H,J=1.0Hz), 3.78(m,2H), 4.63(m,1H), 6.56(d,1H,J=1.0 Hz), 7.38(m,1H),7.61(m,1H), 7.73(m,1H), 9.05(s,1H), 11.1(br,1H)

ESI-MS(m/e): 423[M+H]⁺

PRODUCTION EXAMPLE 84

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-3-([1,3,4]thiadiazol-2-ylsulfanyl)-N-thiazol-2-yl-benzamide

The compound of Production Example 84 was obtained as a colorless oilusing 3-hydroxy-5-iodo-benzoic acid methyl ester, 1-tert-butoxy-2-ol and2-aminothiazole, and using3-(2-tert-butyldimethylsiloxy-1-methyl-propoxy)-5-iodo-N-(thiazol-2-yl)-benzamideobtained in the same manner as Production Example 65 and2-mercapto-[1,3,4]thiadiazole, by the same method as in ProductionExample 74, a corresponding method, or a combination thereof with anordinary method. Removal of the tert-butyldimethylsiloxy group servingas the protective group for the hydroxyl group may be accomplished bythe same method as in Production Example 2, a corresponding method, or acombination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.30(d,3H,J=6.0 Hz), 3.80(m,2H), 4.62(sextet,1H,J=6.0Hz), 7.00(d,1H,J=3.6 Hz), 7.27(d,1H,J=3.6 Hz), 7.40(m,1H), 7.62(m,1H),7.81(m,1H), 9.09(s,1H)

ESI-MS(m/e): 395[M+H]⁺

PRODUCTION EXAMPLE 85

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenylsulfanyl)-N-thiazol-2-yl-benzamide

The compound of Production Example 85 was obtained as a colorless oilusing 3-hydroxy-5-iodo-benzoic acid methyl ester,1-tert-butyldimethylsiloxy-butan-2-ol and 2-aminothiazole, and using3-(2-tert-butyldimethylsiloxy-1-methyl-propoxy)-5-iodo-N-(thiazol-2-yl)-benzamideobtained in the same manner as Production Example 65 and2-mercapto-[1,3,4]thiadiazole, by the same method as in ProductionExample 74, a corresponding method, or a combination thereof with anordinary method. Removal of the tert-butyldimethylsiloxy group servingas the protective group for the hydroxyl group may be accomplished bythe same method as in Production Example 2, a corresponding method, or acombination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.31(d,3H,J=6.2 Hz), 3.07(s,3H), 3.78(m,2H), 4.58(m,1H),7.01(d,1H,J=3.6 Hz), 7.24(m,2H), 7.37(d,2H,J=8.6 Hz), 7.55(m,1H),7.61(m,1H), 7.84(d,2H,J=8.6 Hz), 11.3(br,1H)

ESI-MS(m/e): 465[M+H]⁺

PRODUCTION EXAMPLE 86

Preparation of3-(3-fluoro-phenylthio)-5-(2-hydroxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide

The compound of Production Example 86 was obtained as a white amorphoussubstance using 3-hydroxy-5-iodo-benzoic acid methyl ester,1-(tert-dimethylsiloxy)-2-hydroxypropane and 2-aminothiazole, and using3-(2-tert-butyldimethylsiloxy-1-methyl-ethoxy)-5-iodo-N-(thiazol-2-yl)-benzamideobtained in the same manner as Production Example 65 and3-fluorothiophenol, by the same method as in Production Example 74, acorresponding method, or a combination thereof with an ordinary method.Removal of the tert-butyldimethylsiloxy group serving as the protectivegroup for the hydroxy group may be accomplished by the same method as inProduction Example 2, a corresponding method, or a combination thereofwith an ordinary method.

¹HNMR(CDCl₃)δ: 1.27(d,3H,J=6.2 Hz), 3.75(m,2H), 4.54(m,1H),7.18-6.95(m,4H), 7.21(m,1H), 7.30(m,1H), 7.52-7.40(m,2H)

ESI-MS(m/e): 405[M+H]⁺

PRODUCTION EXAMPLE 87

Preparation of5-(2-hydroxy-1-methylethoxy)-3-(pyridin-4-ylsulfanyl)-N-thiazol-2-yl-benzamide

The compound of Production Example 87 was obtained as a yellow oil using3-hydroxy-5-iodo-benzoic acid methyl ester,1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 2-aminothiazole, andusing3-(2-tert-butyldimethylsiloxy-1-methyl-ethoxy)-5-iodo-N-(thiazol-2-yl)-benzamideobtained in the same manner as Production Example 65 and4-mercaptopyridine, by the same method as in Production Example 74, acorresponding method, or a combination thereof with an ordinary method.Removal of the tert-butyldimethylsiloxy group serving as the protectivegroup for the hydroxy group may be accomplished by the same method as inProduction Example 2, a corresponding method, or a combination thereofwith an ordinary method.

¹HNMR(CDCl₃)δ: 1.36(d,3H,J=6.1 Hz), 3.72(d,2H,J=6.1 Hz),4.68(sextet,1H,J=6.1 Hz), 7.20(m,3H), 7.45(m,1H), 7.54(m,1H),7.75(m,1H), 7.85(m,1H), 8.36(m,2H)

ESI-MS(m/e): 388[M+H]⁺

PRODUCTION EXAMPLE 88

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methyl-pyridin-3-ylsulfanyl)-N-thiazol-2-yl-benzamide

The compound of Production Example 88 was obtained as a white amorphoussubstance using 3-hydroxy-5-iodo-benzoic acid methyl ester,1-(tert-dimethylsiloxy)-2-hydroxypropane and 2-aminothiazole, and using3-(2-tert-butyldimethylsiloxy-1-methyl-ethoxy)-5-iodo-N-(thiazol-2-yl)-benzamideobtained in the same manner as Production Example 65 and3-mercapto-6-methyl-pyridine, by the same method as in ProductionExample 74, a corresponding method, or a combination thereof with anordinary method. Removal of the tert-butyldimethylsiloxy group servingas the protective group for the hydroxy group may be accomplished by thesame method as in Production Example 2, a corresponding method, or acombination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.24(d,3H,J=6.2 Hz), 2.54(s, 3H), 3.72(m,2H), 4.52(m,1H),6.97(m,2H), 7.16(m,2H), 7.33(m,1H), 7.59(m,1H), 8.52(m,1H), 12.0(br,1H)

ESI-MS(m/e): 402[M+H]⁺

PRODUCTION EXAMPLE 89

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(3-methyl-[1,2,4]-thiadiazol-5-yl)-benzamide

After adding 33.4 g (142 mmol) of 4-methanesulfonyl-bromobenzene, 2.67 g(11.9 mmol) of palladium acetate, 5.31 g (17.8 mmol) of2-(di-tert-butylphosphino)biphenyl and 50.3 g (237 mmol) of potassiumphosphate to a solution of 25.0 g (119 mmol) of5-hydroxy-3-methoxymethoxybenzoic acid methyl ester in toluene (375 ml),the reactor was sealed and the mixture was subsequently stirred at 130°C. for 6 hours. Acetic acid ethyl ester was added to the reactionmixture, which was then filtered and concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (hexane:acetic acid ethyl ester=2:1) to obtain 31.0 g of3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl ester(yield: 69%) as a white solid.

After adding 60 ml of trifluoroacetic acid to a solution of 30.9 g (84.3mmol) of the obtained3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl esterin methylene chloride (100 ml) while cooling on ice, the reactionmixture was stirred at room temperature for 4 hours. The reactionmixture was concentrated under reduced pressure, and the obtainedresidue was purified by silica gel column chromatography (hexane:aceticacid ethyl ester=1:1) to obtain 15.2 g of5-hydroxy-3-(4-methanesulfonyl-phenoxy)benzoic acid methyl ester (yield:56%) as a white solid.

After then adding 11.8 g (62.1 mmol) of(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and 16.3 g (62.1 mmol)of triphenylphosphine to a solution of 10.0 g (31.0 mmol) of theobtained 5-hydroxy-3-(4-methanesulfonyl-phenoxy)benzoic acid methylester in tetrahydrofuran (200 ml), 33.8 ml (77.6 mmol) of a solution ofdiethyl azodicarboxylate in 40% toluene was added while cooling on ice,and the mixture was stirred at room temperature for 12 hours. Thereaction mixture was concentrated under reduced pressure, and theobtained residue was purified by silica gel column chromatography(hexane:acetic acid ethyl ester=8:2) to obtain5-((1S)-2-(tert-butyldimethylsiloxy)-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-benzoicacid methyl ester as a yellow oil.

The compound of Production Example 89 was obtained as a colorlessamorphous substance using 200 mg (0.40 mmol) of the obtained5-(1S)-2-(t-butyldimethylsiloxy)-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-benzoicacid methyl ester and 5-amino-3-methyl-[1,2,4]thiadiazole, by the samemethod as in Production Example 2, a corresponding method, or acombination thereof with an ordinary method.

¹HNMR(CH₃OD)δ: 1.30(d,6H,J=6.2 Hz), 2.50(s,3H), 3.12(s,3H),3.68(d,2H,J=5.0 Hz), 4.58-4.63(m,1H), 7.01(s,1H), 7.23(d,2H,J=8.8 Hz),7.36(s,1H), 7.54(s,1H), 7.97(d,2H,J=8.8 Hz)

ESI-MS(m/e): 464[M+H]⁺

PRODUCTION EXAMPLE 90

Preparation ofN-[3-hydroxymethyl-1,2,4-thiadiazol-5-yl]-3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)benzamide

The compound of Production Example 90 was obtained as a colorlessamorphous substance using the3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl esterobtained in Production Example 89, (2R)-1-methoxy-2-propanol and5-amino-3-(t-butyldimethylsiloxymethyl)-[1,2,4]thiadiazole, by the samemethod as in Production Example 89, a corresponding method, or acombination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.34(3H,d,J=6.3 Hz), 3.09(3H,s), 3.41(3H,s),3.49-3.64(2H,m), 4.60-4.72(1H,m), 4.79(2H,s), 6.92(1H,t,J=2.0 Hz),7.16(2H,d,J=8.7 Hz), 7.43(1H,br), 7.93(2H,d,J=8.7 Hz)

ESI-MS(m/e): 494[M+H]⁺

PRODUCTION EXAMPLE 91

Preparation of5-(3-hydroxy-1-methylethoxy)-3-(4-methanesulfonylphenoxy)-N-[5-methyl-1,2,4-thiadiazol-3-yl]benzamide

The compound of Production Example 91 was obtained as a white solidusing the 3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acidmethyl ester obtained in Production Example 89,(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and3-amino-5-methyl-[1,2,4]thiadiazole, by the same method as in ProductionExample 89, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 1.29(d,3H,J=6.3 Hz), 2.76(s,3H), 3.07(s,3H), 3.79(m,2H),4.57(m,1H), 6.81(m,1H), 7.12(d,2H,J=8.8 Hz), 7.17(m,1H), 7.33(m,1H),7.91(d,2H,J=8.8 Hz), 9.27(br,1H)

ESI-MS(m/e): 464[M+H]⁺

PRODUCTION EXAMPLE 92

Preparation of5-(hydroxy-1-methylethoxy)-3-(4-methanesulfonylphenoxy)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)benzamide

The compound of Production Example 92 was obtained as a white amorphoussubstance using the3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl esterobtained in Production Example 89,(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and5-amino-3-methoxy-[1,2,4]thiadiazole, by the same method as inProduction Example 89, a corresponding method, or a combination thereofwith an ordinary method.

¹HNMR(CDCl₃)δ: 1.32(d,3H,J=6.3 Hz), 3.12(s,3H), 3.80(d,2H,J=5.5 Hz),3.99(s,3H), 4.61(m,1H), 6.87(m,1H), 7.17(d,2H,J=8.8 Hz), 7.23(m,1H),7.35(m,1H), 7.96(d,2H,J=8.8 Hz), 11.2(br,1H)

ESI-MS(m/e): 480[M+H]⁺

PRODUCTION EXAMPLE 93

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(1,2,5-thiadiazol-3-yl)benzamide

The compound of Production Example 93 was obtained as a light yellowamorphous substance using the3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl esterobtained in Production Example 89,(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and3-amino-[1,2,5]thiadiazole, by the same method as in Production Example89, a corresponding method, or a combination thereof with an ordinarymethod.

¹HNMR(CDCl₃)δ: 1.34(d,3H,J=6.3 Hz), 1.91(t,1H,J=5.7 Hz), 3.09(s,3H),3.80(m,2H), 4.60(m,1H), 6.89(m,1H), 7.17(d,2H), 7.18(m,1H), 7.35(m,1H),7.96(d,2H,J=8.8 Hz), 8.92(br,1H), 9.32(s,1H)

ESI-MS(m/e): 450[M+H]⁺

PRODUCTION EXAMPLE 94

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(4-trifluoromethyl-thiazol-2-yl)benzamide

The compound of Production Example 94 was obtained as a colorlessamorphous substance using the3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl esterobtained in Production Example 89,(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and2-amino-4-trifluoromethyl-thiazole, by the same method as in ProductionExample 89, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 1.32(d,3H,J=6.2 Hz), 3.11(s,3H), 3.78(d,2H,J=5.1 Hz),4.57-4.63(m,1H), 6.91(s,1H), 7.16-7.17(m,1H), 7.17(d,2H,J=8.8 Hz),7.34-7.36(m,1H), 7.44-7.46(m,1H), 7.96(d,2H,J=8.8 Hz)

ESI-MS(m/e): 517[M+H]⁺

PRODUCTION EXAMPLE 95

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(4,5,6,7-tetrahydrobenzothiazol-2-yl)benzamide

The compound of Production Example 95 was obtained as a colorless oilusing the 3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acidmethyl ester obtained in Production Example 89,(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and2-amino-4,5,6,7-tetrahydrobenzothiazole, by the same method as inProduction Example 89, a corresponding method, or a combination thereofwith an ordinary method.

¹HNMR(CDCl₃)δ: 1.26-1.29(m,3H), 1.82-1.86(m,4H), 2.57-2.72(m,4H),3.09(s,3H), 3.73-3.78(m,2H), 4.54-4.56(m,1H), 6.78-6.81(m,1H),7.09-7.14(m,3H), 7.22-7.29(m,1H), 7.90-7.95(m,2H)

ESI-MS(n/e): 503[M+H]⁺

PRODUCTION EXAMPLE 96

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(pyridazin-3-yl)-benzamide

The compound of Production Example 96 was obtained as a colorlessamorphous substance using the3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl esterobtained in Production Example 89,(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and 3-amino-pyridazine,by the same method as in Production Example 89, a corresponding method,or a combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.30(d,3H,J=5.9 Hz), 2.55(brs,1H), 3.07(s,3H),3.76(m,2H), 4.59(qt,1H,J=5.9,5.5 Hz), 6.83(s,1H), 7.11 (d,2H,J=8.4 Hz),7.24(s,1H), 7.39(s,1H), 7.52(dd,1H,9.2,J=4.8 Hz), 7.90(d,2H,J=8.4 Hz),8.55(d,1H,J=9.2 Hz), 8.93(m,1H), 9.54(brs,1H)

ESI-MS(m/e): 444[M+H]⁺, 442[M−H]⁻

PRODUCTION EXAMPLE 97

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-N-(3-isopropyl-[1,2,4]-triazol-5-yl)-3-(4-methanesulfonylphenoxy)benzamide

The compound of Production Example 97 was obtained as a colorlessamorphous substance using the3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl esterobtained in Production Example 89,(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and5-amino-3-isopropyl-[1,2,4]triazole, by the same method as in ProductionExample 89, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 1.33(d,6H,J=7.3 Hz), 1.35(d,6H,J=7.0 Hz), 3.10(s,3H),3.16-3.21(m,1H), 3.77-3.79(m,2H), 4.57-4.62(m,1H), 6.91(s,1H),7.16(d,2H,J=8.9 Hz), 7.17(d,1H,J=1.7 Hz), 7.35(d,1H,J=1.7 Hz),7.95(d,2H,J=8.9 Hz)

ESI-MS(m/e): 492[M+H]⁺

PRODUCTION EXAMPLE 98

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(3-methyl-[1,2,4]-oxadiazol-5-yl)benzamide

The compound of Production Example 98 was obtained as a colorlessamorphous substance using the3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl esterobtained in Production Example 89,(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and5-amino-3-methyl-[1,2,4]oxadiazole, by the same method as in ProductionExample 89, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 1.28(d,3H,J=5.9 Hz), 2.31(s,3H), 3.08(s,3H),3.75-3.76(m,2H), 4.57-4.58(m,1H), 5.60(brs,1H), 6.84(s,1H),7.09(d,2H,J=8.6 Hz), 7.24(s,1H), 7.35(s,1H), 7.87(d,2H,J=8.6 Hz),10.52(brs,1H)

ESI-MS(m/e): 448[M+H]⁺, 446[M−H]⁻

PRODUCTION EXAMPLE 99

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-thiazol-2-yl]-methanesulfonylphenoxy)benzamide

The compound of Production Example 99 was obtained as a white solidusing the 3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acidmethyl ester obtained in Production Example 89,(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and2-amino-4-(1-hydroxy-1-methyl-ethyl)-thiazole, by the same method as inProduction Example 89, a corresponding method, or a combination thereofwith an ordinary method.

¹HNMR(CDCl₃)δ: 1.33(3H,d,J=6.2 Hz), 1.61(6H,s), 3.08(3H,s),3.75-3.84(2H,m), 4.55-4.65(1H,m), 6.77(1H,s), 6.88(1H,t,J=2.0 Hz),7.16(2H,d,J=8.7 Hz), 7.28(1H,br), 7.45(1H,br), 7.95(2H,d,J=8.7 Hz)

ESI-MS(m/e): 507[M+H]⁺

PRODUCTION EXAMPLE 100

Preparation ofN-(4-cyano-thiazol-2-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)benzamide

The compound of Production Example 100 was obtained as a colorlessamorphous substance using the3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl esterobtained in Production Example 89,(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and2-amino-4-cyano-thiazole, by the same method as in Production Example89, a corresponding method, or a combination thereof with an ordinarymethod.

¹HNMR(CDCl₃)δ: 1.32(d,3H,J=6.2 Hz), 2.48(brs,1H), 3.12(s,3H),3.75-3.85(m,2H), 4.59-4.62(m,1H), 6.88(s,1H), 7.15(d,2H,J=8.8 Hz),7.22(s,1H), 7.38(s,1H), 7.70(s,1H), 7.94(d,2H,J=8.8 Hz), 10.52(brs,1H)

ESI-MS(i/e): 474[M+H]⁺,472[M−H]⁻

PRODUCTION EXAMPLE 101

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

The compound of Production Example 101 was obtained as white crystalsusing the 3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acidmethyl ester obtained in Production Example 89,(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and3-amino-1-methyl-1H-pyrazole, by the same method as in ProductionExample 89, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 1.31(d,3H,J=6.3 Hz), 3.08(s,3H), 3.77(m,2H), 3.81(s,3H),4.57(m,1H), 6.78(m,1H), 6.82(m,1H), 7.11(m,1H), 7.15(d,2H,J=8.9 Hz),7.30(m,2H), 7.93(d,2H,J=8.9 Hz), 8.45(br,1H)

ESI-MS(m/e): 466[M+H]⁺

PRODUCTION EXAMPLE 102

Preparation of5-(1-hydroxymethyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-(pyridin-2-yl)benzamide

The compound of Production Example 102 was obtained as a colorlessamorphous substance using the3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl esterobtained in production Example 89,(2R)-1-(tert-butyldimethylsiloxy)-2-hydroxybutane instead of(2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane, and2-amino-pyridine, by the same method as in Production Example 89, acorresponding method, or a combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.01(t,3H,J=7.7 Hz), 1.76(qd,2H,J=7.7,6.2 Hz),2.10(brs,1H), 3.09(s,3H), 3.78-3.88(m,2H), 4.38-4.44(m,1H), 6.86(s,1H),7.10(dd,1H,J=4.0,8.4 Hz), 7.15(d,2H,J=9.2 Hz), 7.17(s,1H), 7.37(s,1H),7.77(dd,1H,J=8.4,8.4 Hz), 7.93(d,2H,J=9.2 Hz), 8.29(d,1H,J=4.0 Hz),8.34(d,1H,J=8.4 Hz), 8.62(brs,1H)

ESI-MS(m/e): 457[M+H]⁺

PRODUCTION EXAMPLE 103

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(5-methyl-isothiazol-3-yl)benzamide

The compound of Production Example 103 was obtained as a white amorphoussubstance using the3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl esterobtained in Production Example 89,(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and3-amino-5-methyl-isothiazole, by the same method as in ProductionExample 89, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 1.30(d,3H,J=6.2 Hz), 2.58(s,3H), 3.07(s,3H), 3.75(m,2H),4.57(m,1H), 6.82(m,1H), 7.13(d,2H,J=8.9 Hz), 7.15(m,1H), 7.31 (m,1H),7.73(m,1H), 7.92(d,2H,J=8.9 Hz), 9.12(br,1H)

ESI-MS(m/e): 463[M+H]⁺

PRODUCTION EXAMPLE 104

Preparation of5-(3-hydroxy-cyclopentyloxy)-3-(4-methanesulfonylphenoxy)-N-(thiazol-2-yl)benzamide

The compound of Production Example 104 was obtained as a colorlessamorphous substance using the3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl esterobtained in production Example 89,3-(tert-butyldiphenylsiloxy)cyclopentanol instead of(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane, and 2-amino-thiazole,by the same method as in Production Example 89, a corresponding method,or a combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.92(m,6H), 3.08(s,3H), 4.39(s,1H), 4.82-4.84(s,1H),6.82(t,1H,J=1.9 Hz), 7.00(d,1H,J=3.6 Hz), 7.13(d,2H,J=8.6 Hz),7.16(d,1H,J=1.9 Hz), 7.23(d,1H,J=3.6 Hz), 7.34(d,1H,J=1.9 Hz),7.92(d,2H,J=8.6 Hz)

ESI-MS(m/e): 475[M+H]⁺

PRODUCTION EXAMPLE 105

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(5-methoxy-thiazol-2-yl)benzamide

The compound of Production Example 105 was obtained as a white solidusing the 3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acidmethyl ester obtained in Production Example 89,(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and2-amino-5-methoxy-thiazole, by the same method as in Production Example89, a corresponding method, or a combination thereof with an ordinarymethod.

¹HNMR(CDCl₃)δ: 1.28(d,3H,J=6.2 Hz), 3.07(s,3H), 3.75(d,2H,J=5.6 Hz),3.87(s,3H), 4.57(m,1H), 6.52(s,1H), 6.81(m,1H), 7.12(d,2H,J=8.8 Hz),7.17(m,1H), 7.31(m,1H), 7.90(d,2H,J=8.8 Hz), 11.5(br,1H)

ESI-MS(m/e): 479[M+H]⁺

PRODUCTION EXAMPLE 106

Preparation of5-(1-hydroxymethyl-2-methyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-(thiazol-2-yl)benzamide

The compound of Production Example 106 was obtained as a white amorphoussubstance using the3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl esterobtained in production Example 89,1-(tert-butyldimethylsiloxy)-3-methyl-butan-2-ol instead of(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane, and 2-amino-thiazole,by the same method as in Production Example 89, a corresponding method,or a combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 0.97(m,6H), 2.05(m,1H), 3.07(s,3H), 3.83(m,2H),4.22(m,1H), 6.84(m,1H), 6.96(d,1H,J=3.7 Hz), 7.11(d,2H,J=8.9 Hz),7.18(m,1H), 7.23(d,1H,J=3.7 Hz), 7.39(m,1H), 7.91(d,2H,J=8.8 Hz),12.0(br,1H)

ESI-MS(m/e): 477[M+H]⁺

PRODUCTION EXAMPLE 107

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(1H-[1,2,3]triazol-4-yl)benzamide

The compound of Production Example 107 was obtained as a colorlessamorphous substance using the3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl esterobtained in Production Example 89,(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and4-amino-1H-[1,2,3]triazole, by the same method as in Production Example89, a corresponding method, or a combination thereof with an ordinarymethod.

¹HNMR(CDCl₃)δ: 1.31(d,3H,J=6.2 Hz), 3.11 (s,3H), 3.34(s,1H),3.67-3.68(m,2H), 4.56-4.60(m,2H), 6.93(s,1H), 7.21(d,2H,J=8.8 Hz),7.25(s,1H), 7.43(s,1H), 7.94(d,2H,J=8.8 Hz), 8.08(brs,1H)

ESI-MS(m/e): 433[M+H]⁺,431 [M−H]⁻

PRODUCTION EXAMPLE 108

Preparation ofN-(1-acetyl-1H-pyrazol-3-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)benzamide

The compound of Production Example 108 was obtained as a white amorphoussubstance using the3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl esterobtained in Production Example 89,(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and3-amino-1-acetyl-1H-pyrazole, by the same method as in ProductionExample 89, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 1.36(d,3H,J=6.3 Hz), 2.65(s,3H), 3.12(s,3H), 3.82(m,2H),4.61(m,1H), 6.89(m,1H), 7.16-7.22(m,4H), 7.35(m,1H), 7.98(d,2H,J=8.8Hz), 8.22(d,1H,J=3.0 Hz), 8.46(br,1H)

ESI-MS(m/e): 474[M+H]⁺

PRODUCTION EXAMPLE 109

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(pyrazol-3-yl)benzamide

The compound of Production Example 109 was obtained as a white amorphoussubstance using the3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl esterobtained in Production Example 89,(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and 3-amino-pyrazole, bythe same method as in Production Example 89, a corresponding method, ora combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.26(d,3H,J=6.3 Hz), 3.05(s,3H), 3.73(m,2H), 4.52(m,1H),6.75(m,2H), 7.06(d,2H,J=8.8 Hz), 7.14(m,1H), 7.32(m,1H), 7.46(m,1H),7.85(d,2H,J=8.8 Hz), 9.72(br,1H)

ESI-MS(m/e): 432[M+H]⁺

PRODUCTION EXAMPLE 110

Preparation ofN-(5,6-dihydro-4H-cyclopentathiazol-2-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)benzamide

The compound of Production Example 110 was obtained as a colorlessamorphous substance using the3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl esterobtained in Production Example 89,(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and2-amino-5,6-dihydro-4H-cyclopentanethiazole, by the same method as inProduction Example 89, a corresponding method, or a combination thereofwith an ordinary method.

¹HNMR(CDCl₃)δ: 1.28(d,3H,J=6.2 Hz), 2.44(tt,2H,J=7.0,7.0 Hz), 2.61(t,2H,J=7.0 Hz), 2.90(t,2H,J=7.0 Hz), 3.08(s,3H), 3.70-3.76(m,2H),4.51-4.55(m,1H), 6.76(s,1H), 7.10(d,2H,J=8.8 Hz), 7.12(s,1H),7.28(s,1H), 7.90(d,2H,J=9.2 Hz)

ESI-MS(m/e): 489[M+H]⁺,487[M−H]⁻

PRODUCTION EXAMPLE 111

Preparation of5-(1-hydroxymethyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

The compound of Production Example 111 was obtained as a white amorphoussubstance using the3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl esterobtained in production Example 89 and(2R)-1-(tert-butyldimethylsiloxy)-butan-2-ol instead of(2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane, and3-amino-1-methyl-1H-pyrazole, by the same method as in ProductionExample 89, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 0.93(t,3H,J=7.5 Hz), 1.69(quintet,1H,J=7.5 Hz),2.75(t,1H,J=6.2 Hz), 3.06(s,3H), 3.74(s,3H), 3.70-3.80(m,2H),4.33(m,1H), 6.77(m,2H), 7.09(d,2H,J=8.8 Hz), 7.11(m,1H), 7.27(m,2H),7.99(d,2H,J=8.8 Hz), 9.03(br,1H)

ESI-MS(m/e): 460[M+H]⁺

PRODUCTION EXAMPLE 112

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(thieno[3,2-d]thiazol-2-yl)benzamide

The compound of Production Example 112 was obtained as a colorlessamorphous substance using the3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl esterobtained in Production Example 89,(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and2-amino-thieno[3,2-d]thiazole, by the same method as in ProductionExample 89, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 1.30(d,3H,J=6.2 Hz), 2.05(brs,1H), 3.09(s,3H),3.76-3.78(m,2H), 4.55-4.57(m,1H), 6.84(s,1H), 7.11(d,2H,J=8.8 Hz),7.11(s,1H), 7.19(s,1H), 7.36(s,1H), 7.38(s,1H), 7.92(d,2H,J=8.8 Hz),10.42(brs,1H)

ESI-MS(m/e): 505[M+H]⁺,503[M−H]⁻

PRODUCTION EXAMPLE 113

Preparation of3-(3-fluoro-4-methanesulfonylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

The compound of Production Example 113 was obtained as white crystalsusing 3-(3-fluoro-4-methanesulfonylphenoxy)-5-hydroxy-benzoic acidmethyl ester obtained in the same manner as Production Example 42,(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and3-amino-1-methyl-1H-pyrazole, by the same method as in ProductionExample 2, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 1.31(d,3H,J=6.3 Hz), 2.20(t,1H,J=6.5 Hz), 3.23(s,3H),3.77(m,2H), 3.80(s,3H), 4.57(sextet,1H,J=4.5 Hz), 6.79-6.93(m,4H),7.14(m,1H), 7.30(m,1H), 7.33(m,1H), 7.92(t,1H,J=8.4 Hz), 8.57(br,1H)

ESI-MS(m/e): 464[M+H]⁺

PRODUCTION EXAMPLE 114

Preparation of3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-N-(pyrazol-3-yl)benzamide

The compound of Production Example 114 was obtained as a white amorphoussubstance using the3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl esterobtained in Production Example 89, (2R)-1-methoxy-2-propanol and3-amino-pyrazole, by the same method as in Production Example 89, acorresponding method, or a combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.32(d,3H,J=6.2 Hz), 3.05(s,3H), 3.39(s,3H),3.50-3.60(m,2H), 4.60(m,1H), 6.80(t,1H,J=2.2 Hz), 6.85(d,1H,J=2.2 Hz),7.09(d,2H,J=8.8 Hz), 7.16(t,1H,J=2.2 Hz), 7.39(t,1H,J=2.2 Hz),7.47(d,1H,J=2.2 Hz), 7.87(d,2H,J=8.8 Hz), 9.80(br,1H)

ESI-MS(m/e): 446[M+H]⁺

PRODUCTION EXAMPLE 115

Preparation of3-(4-cyano-phenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

The compound of Production Example 115 was obtained as a colorlessamorphous substance using 5-hydroxy-3-methoxymethoxybenzoic acid methylester and p-cyanophenylboric acid, and using3-(4-cyano-phenoxy)-5-methoxymethoxy-benzoic acid methyl ester obtainedin the same manner as Production Example 1,(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and3-amino-1-methyl-1-pyrazole, by the same method as in Production Example89, a corresponding method, or a combination thereof with an ordinarymethod.

¹HNMR(CDCl₃)δ: 1.30(d,3H,J=6.2 Hz), 2.31(brs,1H), 3.76-3.79(m,2H),3.79(s,3H), 4.54(qt,1H,J=6.2 Hz,4.0 Hz), 6.77(d,1H,J=2.2 Hz),6.78(s,1H), 7.07(d,2H,J=8.8 Hz), 7.09(s,1H), 7.27(s,1H), 7.28(d,1H,J=2.2Hz), 7.63(d,2H,8.8 Hz), 8.64(brs,1H)

ESI-MS(m/e): 393[M+H]⁺

PRODUCTION EXAMPLE 116

Preparation of3-(4-ethylsulfonylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

The compound of Production Example 116 was obtained as a colorlessamorphous substance using 3-(4-ethylthio-phenoxy)-5-hydroxy-benzoic acidmethyl ester obtained by deprotection of the methoxymethyl group of3-(4-ethylthio-phenoxy)-5-methoxymethoxy-benzoic acid methyl esterobtained using 5-hydroxy-3-methoxymethoxybenzoic acid methyl ester andp-ethylthiophenylboric acid according to the same method as inProduction Example 1, (2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropaneand 3-amino-1-methyl-1H-pyrazole, by the same method as in ProductionExample 2, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 1.32(d,3H,J=6.2 Hz), 1.33(t,3H,J=7.7 Hz), 2.05(brs, 1H),3.14(q,2H,J=7.7 Hz), 3.75-3.79(m,2H), 3.81(s,3H), 4.56(qt,1H,J=6.2,3.7Hz), 6.78(s,1H), 6.81(d,1H,J=2.2 Hz), 7.11(s,1H), 7.12(d,2H,J=8.8 Hz),7.28(d,1H,J=2.2 Hz), 7.28(s,1H), 7.87(d,2H,J=8.8 Hz), 8.41(brs,1H)

ESI-MS(m/e): 460[M+H]⁺,458[M−H]⁻

PRODUCTION EXAMPLE 117

Preparation of3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

After adding 178 mg (0.71 mmol) of 5-bromo-2-ethanesulfonylpyridine and232 mg (0.71 mmol) of cesium carbonate to a solution of 100 mg (0.47mmol) of 5-hydroxy-3-methoxymethoxybenzoic acid methyl ester inN,N-dimethylformamide (1.0 ml), the mixture was stirred at 100° C. for2.5 hours under a nitrogen atmosphere. Acetic acid ethyl ester andaqueous ammonium chloride were added to the reaction mixture, theaqueous layer was extracted with acetic acid ethyl ester, and then theorganic layer was washed with brine, dried and concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (hexane:acetic acid ethyl ester=1:1) to obtain 165 mg of3-(6-ethanesulfonyl-pyridin-3-yloxy)-5-methoxymethoxybenzoic acid methylester (yield: 91%) as a colorless oil.

After adding 30.0 ml of trifluoroacetic acid to a solution of 11.8 g(30.9 mmol) of the obtained ester compound in methylene chloride (50.0ml), the reaction mixture was stirred at room temperature for 5 hours.The reaction mixture was concentrated under reduced pressure, and theobtained residue was purified by silica gel column chromatography(hexane:acetic acid ethyl ester =2:1) to obtain 8.86 g of3-(6-ethanesulfonyl-pyridin-3-yloxy)-5-hydroxybenzoic acid methyl ester(yield: 85%) as a colorless oil.

After adding 1.02 g (5.34 mmol) of(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and 1.40 g (5.34 mmol)of triphenylphosphine to a solution of 1.00 g (2.97 mmol) of theobtained phenol compound in tetrahydrofuran (30.0 ml), 2.42 ml (5.34mmol) of a solution of diethyl azodicarboxylate in 40% toluene was addedwhile cooling on ice, and the mixture was stirred at room temperaturefor 1 hour. The reaction mixture was concentrated under reducedpressure, and the obtained residue was purified by silica gel columnchromatography (hexane:acetic acid ethyl ester=3:2) to obtain 1.31 g of3-((1S)-2-(t-butyldimethylsiloxy)-1-methyl-ethoxy)-5-(6-ethanesulfonyl-pyridin-3-yloxy)-benzoicacid methyl ester (yield: 87%) as a colorless oil.

The compound of Production Example 117 was obtained as a colorlessamorphous substance using the obtained3-((1S)-2-(t-butyldimethylsiloxy)-1-methyl-ethoxy)-5-(6-ethanesulfonyl-pyridin-3-yloxy)-benzoicacid methyl ester and 3-amino-1-methylpyrazole, by the same method as inProduction Example 2, a corresponding method, or a combination thereofwith an ordinary method.

¹HNMR(CDCl₃)δ: 1.32(d,3H,J=6.2 Hz), 1.33(t,3H,J=7.3 Hz), 3.40(q,2H,J=7.3Hz), 3.75-3.77(m,2H), 3.81(s,3H), 4.54-4.59(m,1H,J=6.2,-Hz),6.76(d,1H,J=2.2 Hz), 6.81 (dd,1H,J=2.2,2.2 Hz), 7.14(dd,1H,J=2.2,1.7Hz), 7.28(d,1H,J=2.2 Hz), 7.32(d,1H,J=2.2,1.7 Hz), 7.43(dd,1H,J=8.8,2.6Hz), 8.05(d,1H,J=8.8 Hz), 8.45(brs,1H), 8.47(d,1H,J=2.6 Hz)

ESI-MS(m/e): 461 [M+H]⁺,459[M−H]⁻

PRODUCTION EXAMPLE 118

Preparation of5-(3-hydroxy-1-methyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

The compound of Production Example 118 was obtained as a colorlessamorphous substance using the3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl esterobtained in Production Example 89,4-(tert-butyldimethylsiloxy)-butan-2-ol and3-amino-1-methyl-1H-pyrazole, by the same method as in ProductionExample 89, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 1.37(3H,d,J=6.2 Hz), 1.88-1.93(2H,m), 1.96-2.09(1H,m),3.08(3H,s), 3.78-3.87(2H,m), 3.81(3H,s), 6.78(1H,d,J=2.0 Hz),6.81(1H,t,J=2.1 Hz), 7.11-7.18(3H,m), 7.29(1H,d,J=2.2 Hz), 7.35(1H,br),7.92(2H,d,J=9.0 Hz), 8.51(1H,br)

ESI-MS(m/e): 460[M+H]⁺

PRODUCTION EXAMPLE 119

Preparation of3-(4-ethanesulfonylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)benzamide

The compound of Production Example 119 was obtained as a colorlessamorphous substance using 3-(4ethylthio-phenoxy)-5-hydroxy-benzoic acidmethyl ester obtained by deprotection of the methoxymethyl group of3-(4-ethylthio-phenoxy)-5-methoxymethoxy-benzoic acid methyl esterobtained using 5-hydroxy-3-methoxymethoxybenzoic acid methyl ester andp-ethylthiophenylboric acid according to the same method as inProduction Example 1, (2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropaneand 3-amino-isoxazole, by the same method as in Production Example 2, acorresponding method, or a combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.32(t,3H,J=7.4 Hz), 1.32(d,3H,J=6.3 Hz), 3.13(q,2H,J=7.4Hz), 3.76-3.79(m,2H), 4.56-4.62(m,1H), 6.87(t,1H,J=1.8 Hz),7.14(d,2H,J=8.7 Hz), 7.16(d,1H,J=1.8 Hz), 7.26(d,1H,J=1.8 Hz),7.31(s,1H), 7.93(d,2H,J=8.7 Hz), 8.34(s,1H),

ESI-MS(m/e): 477[M+H]⁺

PRODUCTION EXAMPLE 120

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-3-(4-isopropylsulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

The compound of Production Example 120 was obtained as a colorlessamorphous substance using 3-(4-isopropylthio-phenoxy)-5-hydroxy-benzoicacid methyl ester obtained by deprotection of the methoxymethyl group of3-(4-isopropylthio-phenoxy)-5-methoxymethoxy-benzoic acid methyl esterobtained using 5-hydroxy-3-methoxymethoxybenzoic acid methyl ester andp-isopropylthiophenylboric acid according to the same method as inProduction Example 1, (2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropaneand 3-amino-1-methyl-1H-pyrazole, by the same method as in ProductionExample 2, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 1.32(d,3H,J=6.2 Hz), 1.32(d,6H,J=7.0 Hz),3.20(septet,1H,J=7.0 Hz), 3.76-3.77(m,2H), 3.79(s,3H),4.55(qt,1H,J=6.2,4.0 Hz), 6.79(d,1H,J=2.2 Hz), 6.80(s,1H),7.10(d,2H,J=8.8 Hz), 7.13(s,1H), 7.29(d,1H,J=2.2 Hz), 7.29(s,1H),7.83(d,2H,J=8.8 Hz), 8.61(brs,1H)

ESI-MS(m/e): 474[M+H]⁺,472[M−H]⁻

PRODUCTION EXAMPLE 121

Preparation of5-(2-hydroxy-l-methyl-ethoxy)-N-(4-hydroxy-4-methyl-4,5,6,6a-tetrahydro-3aH-cyclopentathiazol-2-yl)-3-(4-methanesulfonylphenoxy)benzamide

The compound of Production Example 121 was obtained as a colorlessamorphous substance using the3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl esterobtained in Production Example 89,(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and2-amino-4-hydroxy-4-methyl-4,5,6,6a-tetrahydro-3aH-cyclopentathiazole,by the same method as in Production Example 89, a corresponding method,or a combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.27-1.33(3H,m), 1.60(3H,s), 2.56(2H,m), 2.75-3.07(2H,m),3.08(3H,s), 3.74-3.82(2H,m), 4.53-4.65(1H,m), 6.75-6.83(1H,m),7.11-7.20(3H,m), 7.29-7.35(1H,m), 7.93(2H,d,J=8.9 Hz)

ESI-MS(m/e): 519[M+H]⁺

PRODUCTION EXAMPLE 122

Preparation of3-(4-dimethylcarbamoyl-phenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

The compound of Production Example 122 was obtained as a colorlessamorphous substance by the same method as in Production Example 2, acorresponding method, or a combination thereof with an ordinary method,using (2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane,3-amino-1-methyl-1H-pyrazole and3-(4-dimethylcarbamoyl-phenoxy)-5-hydroxy-benzoic acid methyl esterobtained by deprotection of the methoxymethyl group of3-(4-dimethylcarbamoyl-phenoxy)-5-methoxymethoxy-benzoic acid methylester obtained by converting the formyl group of3-(4-formyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl ester obtainedin the same manner as Production Example 1, using5-hydroxy-3-methoxymethoxybenzoic acid methyl ester andp-formylphenylboric acid, to carboxyl, followed by condensation withdimethylamine.

¹HNMR(CDCl₃)δ: 1.33(d,3H,J=6.2 Hz), 2.11(brs,1H), 3.08(s,3H),3.13(s,3H), 3.74-3.81(m,2H), 3.83(s,3H), 4.54-4.58(m,1H), 6.77(s,1H),6.80(s,1H), 7.06(d,2H,J=7.7 Hz), 7.10(s,1H), 7.26(s,1H), 7.30(s,1H),7.46(d,2H,J=7.7 Hz), 8.49(brs,1H)

ESI-MS(m/e): 439[M+H]⁺,437[M−H]⁻

PRODUCTION EXAMPLE 123

Preparation of3-(4-acetylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

The compound of Production Example 123 was obtained as a colorlessamorphous substance by the same method as in Production Example 2, acorresponding method, or a combination thereof with an ordinary method,using (2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane,3-amino-1-methyl-1H-pyrazole and 3-(4-acetyl-phenoxy)-5-hydroxy-benzoicacid methyl ester obtained by deprotection of the methoxymethyl group of3-(4-acetyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl ester obtainedby reaction of the formyl group of3-(4-formyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl ester obtainedby the same method as in Production Example 122 with methylmagnesiumbromide, followed by oxidation.

¹HNMR(CDCl₃)δ: 1.30(d,3H,J=6.2 Hz), 2.59(s,3H), 3.75-3.76(m,2H),3.79(s,3H), 4.52-4.56(m,1H,J=6.2,-Hz), 6.78(d,1H,J=2.2Hz,dd,1H,J=2.2,1.8 Hz), 7.04(d,2H,J=8.8 Hz), 7.07(dd,1H,J=1.8,1.8 Hz),7.25(dd,1H,J=2.2,1.8 Hz), 7.26(d,1H,J=2.2 Hz), 7.95(d,2H,J=8.8 Hz),8.52(brs,1H)

ESI-MS(m/e): 410[M+H]⁺,408[M−H]⁻

PRODUCTION EXAMPLE 124

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-3-(1,3,4-thiadiazol-2-ylsulfanyl)benzamide

The compound of Production Example 124 was obtained as a colorlessamorphous substance using 3-hydroxy-5-iodobenzoic acid methyl ester,1-tert-dimethylsiloxy-2-hydroxypropane, 2-mercapto-[1,3,4]thiadiazoleand 3-amino-1-methyl-1H-pyrazole, by the same method as in ProductionExample 74 or 82, a corresponding method, or a combination thereof withan ordinary method.

¹HNMR(CDCl₃)δ: 1.31(3H,d,J=6.2 Hz), 3.74-3.79(2H,m), 3.82(3H,s),4.54-4.63(1H,m), 6.78(1H,d,J=2.2 Hz), 7.30(1H,d,J=2.3 Hz), 7.39(1H,m),7.54(1H,m), 7.69(1H,m), 8.55(1H,br), 9.05(1H,s)

ESI-MS(m/e): 392[M+H]⁺

PRODUCTION EXAMPLE 125

Preparation ofN-(1-ethyl-1H-pyrazol-3-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)benzamide

The compound of Production Example 125 was obtained as a white amorphoussubstance using the3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl esterobtained in Production Example 89,(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and3-amino-1-ethyl-1H-pyrazole, by the same method as in Production Example89, a corresponding method, or a combination thereof with an ordinarymethod.

¹HNMR(CDCl₃)δ: 1.30(d,3H,J=6.2 Hz), 1.43(t,3H,J=7.3 Hz), 3.07(s,3H),3.76(m,2H), 4.05(q,2H,J=7.3 Hz), 4.56(m,1H), 6.79(m,2H), 7.12(d,2H,J=8.8Hz), 7.14(m,1H), 7.30(m,1H), 7.33(m,1H), 7.92(d,2H,J=8.8 Hz),8.70(br,1H)

ESI-MS(m/e): 460[M+H]⁺

PRODUCTION EXAMPLE 126

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

The compound of Production Example 126 was obtained as a white amorphoussubstance using 5-hydroxy-3-methoxymethoxybenzoic acid methyl ester,5-bromo-2-methanesulfonylpyridine,(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and3-amino-1-methyl-1H-pyrazole, by the same method as in ProductionExample 117, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 1.29(d,3H,J=6.3 Hz), 3.22(s,3H), 3.75(m,2H), 3.78(s,3H),4.55(m,1H), 6.75(m,1H) 6.78(m,1H), 7.11(m,1H), 7.26(m,1H), 7.29(m,1H),7.42(dd,1H,J=2.9,8.5 Hz), 8.03(d,1H,J=8.5 Hz), 8.44(d,1H,J=2.9 Hz),8.65(br,1H)

ESI-MS(m/e): 447[M+H]⁺

PRODUCTION EXAMPLE 127

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methoxycarbonylaminomethyl-phenoxy)-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide

The compound of Production Example 127 was obtained as a colorlessamorphous substance by the same method as in Production Example 2, acorresponding method, or a combination thereof with an ordinary method,using (2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane,5-amino-3-methyl-[1,2,4]-thiadiazole and3-(4-methoxycarbonylaminomethylphenoxy)-5-hydroxy-benzoic acid methylester obtained by deprotection of the methoxymethyl group of3-(4-methoxycarbonylaminomethylphenoxy)-5-methoxymethoxy-benzoic acidmethyl ester obtained by the same method as in Production Example 59,using 5-hydroxy-3-methoxymethoxybenzoic acid methyl ester instead of5-hydroxy-3-isopropoxybenzoic acid methyl ester.

¹HNMR(CDCl₃)δ: 1.29(d,3H,J=6.2 Hz), 2.45(s,3H), 3.71(s,3H),3.73-3.78(m,2H), 4.35(d,2H,J=6.2 Hz), 4.50-4.57(m,1H,J=6.2 Hz,-),5.08(brs,1H), 6.76(s,1H), 6.97(d,2H,J=8.3 Hz), 7.01(s,1H), 7.16(s,1H),7.27(d,2H,J=8.3 Hz), 10.8(brs,1H)

ESI-MS(m/e): 495[M+Na]⁺,473[M+H]⁺,471[M−H]⁻

PRODUCTION EXAMPLE 128

Preparation of5-(1-hydroxymethyl-propoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

The compound of Production Example 128 was obtained as a colorlessamorphous substance using 5-hydroxy-3-methoxymethoxybenzoic acid methylester, 5-bromo-2-methanesulfonylpyridine,(2S)-1-(tert-butyldimethylsiloxy)-2-hydroxybutane and3-amino-1-methyl-1H-pyrazole, by the same method as in ProductionExample 117, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 0.99(t,3H,J=7.5 Hz), 1.70-1.77(m,2H), 3.24(s,3H),3.79-3.82(m,5H), 4.36-4.40(m,1H), 6.78(d,1H,J=1.8 Hz), 6.85(d,1H,J=1.8Hz), 7.13(s,1H), 7.29(d,1H,J=2.3 Hz), 7.34(d,1H,J=2.3 Hz),7.46(dd,1H,J=2.6,8.9 Hz), 8.08(d,1H,J=8.9 Hz), 8.48(d,1H,J=2.6 Hz)

ESI-MS(m/e): 461[M+H]⁺

PRODUCTION EXAMPLE 129

Preparation of3-(6-methanesulfonylpyridin-3-yloxy)-5-(1-methoxymethyl-propoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

The compound of Production Example 129 was obtained as a colorlessamorphous substance using 5-hydroxy-3-methoxymethoxybenzoic acid methylester, 5-bromo-2-methanesulfonylpyridine, (2S)-1-methoxy-2-hydroxybutaneand 3-amino-1-methyl-1H-pyrazole, by the same method as in ProductionExample 117, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 0.99(t,3H,J=7.4 Hz), 1.74-1.79(m,2H), 3.24(s,3H),3.37(s,3H), 3.56-3.57(m,2H), 3.79(s,3H), 4.37-4.40(m,1H), 6.79(s,1H),6.87(t,1H,J=1.2 Hz), 7.14(s,1H), 7.29(d,1H,J=1.2 Hz), 7.34(d,1H,J=1.2Hz), 7.45(dd,1H,J=2.0,8.6 Hz), 8.06(d,1H,J=8.6 Hz), 8.48(d,1H,J=2.0 Hz)

ESI-MS(m/e): 475[M+H]⁺

PRODUCTION EXAMPLE 130

Preparation of5-isopropoxy-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

The compound of Production Example 130 was obtained as a white amorphoussubstance using 5-hydroxy-3-methoxymethoxybenzoic acid methyl ester,5-bromo-2-methanesulfonylpyridine, 2-hydroxypropane and3-amino-1-methyl-1H-pyrazole, by the same method as in ProductionExample 117, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 1.35(d,6H,J=6.2 Hz), 3.22(s,3H), 3.77(s,3H),6.75(septe,1H,J=6.2 Hz), 6.74(m,1H), 6.76(m,1H), 7.08(m,1H), 7.24(m,1H),7.26(m,1H), 7.41(dd,1H,J=2.9,8.8 Hz), 8.03(d,1H,J=8.8 Hz),8.44(d,1H,J=2.9 Hz), 8.64(br,1H)

ESI-MS(m/e): 431 [M+H]⁺

PRODUCTION EXAMPLE 131

Preparation of5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

The compound of Production Example 131 was obtained as a white amorphoussubstance using 5-hydroxy-3-methoxymethoxybenzoic acid methyl ester,5-bromo-2-methanesulfonylpyridine, 1,3-difluoro-2-propanol and3-amino-1-methyl-1H-pyrazole, by the same method as in ProductionExample 117, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 3.23(s,3H), 3.75(s,3H), 4.55-4.61(m,2H), 4.61-4.80(m,3H),6.75(m,1H), 6.88(m,1H), 7.18(m,1H), 7.27(m,1H), 7.34(m,1H),7.43(dd,1H,J=2.4,8.4 Hz), 8.04(d,1H), 8.44(d,1H,J=2.4 Hz), 8.84(br,1H)

ESI-MS(n/e): 467[M+H]⁺

PRODUCTION EXAMPLE 132

Preparation of3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)benzamide

The compound of Production Example 132 was obtained as a colorlessamorphous substance using 5-hydroxy-3-methoxymethoxybenzoic acid methylester, 5-bromo-2-ethanesulfonylpyridine,(2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and3-amino-isoxazole, by the same method as in Production Example 117, acorresponding method, or a combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.31(d,3H,J=6.2 Hz), 1.32(t,3H,J=7.3 Hz), 2.22(brs,1H),3.40(q,2H,J=7.3 Hz), 3.75-3.77(m,2H), 4.56-4.61(m,1H,J=6.2,-Hz),6.86(d,1H,J=2.2 Hz), 7.17(d,1H,J=2.2 Hz), 7.26(d,1H,0.7 Hz),7.40(d,1H,J=2.2 Hz), 7.43(dd,1H,J=8.8,2.9 Hz), 8.04(d,1H,J=8.8 Hz),8.26(d,1H,J=0.7 Hz), 8.46(d,1H,J=2.9 Hz), 9.83(brs,1H)

ESI-MS(m/e): 448[M+H]⁺,446[M−H]⁻

PRODUCTION EXAMPLE 133

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenylsulfanyl)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

The compound of Production Example 133 was obtained as a colorlessamorphous substance using 3-hydroxy-5-iodobenzoic acid methyl ester,(2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane,4-methanesulfonylbenzenethiol and 3-amino-1-methyl-1H-pyrazole, by thesame method as in Production Example 74 or 82, a corresponding method,or a combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.30(3H,d,J=6.2 Hz), 3.05(3H,s), 3.74-3.79(2H,m),3.81(3H,s), 4.52-4.63(1H,m), 6.78(1H,d,J=2.3 Hz), 7.21(1H,m),7.30(1H,d,J=2.2 Hz), 7.34(2H,d,J=8.6 Hz), 7.47-7.50(1H,m),7.51-7.54(1H,m), 7.82(2H,d,J=8.6 Hz), 8.53(1H,br)

ESI-MS(m/e): 392[M+H]⁺

PRODUCTION EXAMPLE 134

Preparation of 5cyclopropyloxy-3-(4-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

The compound of Production Example 134 was obtained as a colorless oilby the same method as in Production Example 1, a corresponding method,or a combination thereof with an ordinary method, using5-methoxymethoxy-3-vinyloxy-benzoic acid methyl ester obtained byreacting 5-hydroxy-3-methoxymethoxybenzoic acid methyl ester,tetravinyltin and copper acetate, and then using p-methylthiophenylboricacid, 3-amino-1-methyl-1H-pyrazole, and3-cyclopropyloxy-5-methoxymethoxy-benzoic acid methyl ester obtained byreaction between diethylzinc and diiodomethane.

¹HNMR(CDCl₃)δ: 0.70-0.85(m,4H), 3.08(s,3H), 3.78(m,1H), 3.79(s,3H),6.78(m,1H), 6.91(m,1H), 7.10-7.14(m,3H), 7.27(m,1H), 7.41(m,1H),7.90(d,2H,J=8.8 Hz), 8.52(br,1H)

ESI-MS(m/e): 428[M+H]⁺

PRODUCTION EXAMPLE 135

Preparation of3-(6-methanesulfonylpyridin-3-yloxy)-5-(1-methoxymethyl-propoxy)-N-(pyrazol-3-yl)benzamide

The compound of Production Example 135 was obtained as a colorlessamorphous substance using 5-hydroxy-3-methoxymethoxybenzoic acid methylester, 5-bromo-2-methanesulfonylpyridine, (2R)-1-methoxy-2-hydroxybutaneand 3-amino-pyrazole, by the same method as in Production Example 117, acorresponding method, or a combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 0.98(t,3H,J=7.4 Hz), 1.69-1.78(m,2H), 3.22(s,3H),3.38(s,3H), 3.58-3.59(m,2H), 4.37-4.43(m,1H), 6.84-6.85(m,2H),7.20(s,1H), 7.41-7.49(m,3H), 8.04(d,1H,J=8.6 Hz), 8.45(d,1H,J=2.6 Hz),9.92(brs,1H)

ESI-MS(m/e): 461[M+H]⁺

PRODUCTION EXAMPLE 136

Preparation of5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

The compound of Production Example 136 was obtained as a colorlessamorphous substance using the3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl esterobtained in Production Example 89, 1,3-difluoro-2-propanol and3-amino-1-methyl-1H-pyrazole, by the same method as in ProductionExample 89, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 3.09(s,3H), 3.77(s,3H), 4.59-4.76(m,5H), 6.78(s,1H),6.89(t,1H,J=2.0 Hz), 7.13(d,2H,J=8.6 Hz), 7.18(s,1H), 7.29(d,1H,J=2.0Hz), 7.33(d,1H,J=2.0 Hz), 7.93(d,2H,J=8.6 Hz), 8.76(brs,1H)

ESI-MS(m/e): 466[M+H]⁺

PRODUCTION EXAMPLE 137

Preparation of3-(6-ethanesulfonylpyridin-3-yloxy)-5-(1-hydroxymethyl-propoxy)-N(1-methyl-1H-pyrazol-3-yl)benzamide

The compound of Production Example 137 was obtained as a colorlessamorphous substance using 5-hydroxy-3-methoxymethoxybenzoic acid methylester, 5-bromo-2-ethanesulfonylpyridine,(2R)-1-(tert-butyldimethylsiloxy)-2-hydroxybutane and3-amino-1-methyl-1H-pyrazole, by the same method as in ProductionExample 117, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 0.97(t,3H,J=7.4 Hz), 1.32(t,3H,J=7.4 Hz),1.67-1.84(m,2H), 3.40(q,2H,J=7.4 Hz), 3.74-3.84(m,5H), 4.33-4.40(m,1H),6.77(s,1H), 6.79(s,1H), 7.15(s,1H), 7.28(s,1H), 7.33(s,1H),7.43(dd,1H,J=2.6,8.8 Hz), 8.05(d,1H,J=8.8 Hz), 8.47(d,1H,J=2.6 Hz)

ESI-MS(n/e): 475[M+H]⁺

PRODUCTION EXAMPLE 138

Preparation of5-(6-ethanesulfonylpyridin-3-yloxy)-3-(2-methoxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

The compound of Production Example 138 was obtained as a colorlessamorphous substance using 5-hydroxy-3-methoxymethoxybenzoic acid methylester, 5-bromo-2-ethanesulfonylpyridine, (2R)-2-hydroxy-1-methoxypropaneand 3-amino-1-methyl-1H-pyrazole, by the same method as in ProductionExample 117, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 1.34(t,3H,J=7.3 Hz), 1.34(d,3H,J=4.0 Hz), 3.40(s,3H),3.41(q,2H,J=7.3 Hz), 3.49-3.60(m,2H), 3.80(s,3H), 4.60(qt,1H,J=4.0,6.2Hz), 6.78(s,1H), 6.83(d,1H,J=2.2 Hz), 7.14(s,1H), 7.28(d,1H,J=2.2 Hz),7.31(s,1H), 7.42(dd,1H,J=8.4,2.6 Hz), 8.05(d,1H,J=8.4 Hz),8.48(d,1H,J=2.6 Hz), 8.49(brs,1H)

ESI-MS(m/e): 475[M+H]⁺,473[M−H]⁻

PRODUCTION EXAMPLE 139

Preparation of2-[3-(4-methanesulfonylphenoxy)-5-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-phenoxy]propionicacid-tert-butyl ester

The compound of Production Example 139 was obtained as a colorlessamorphous substance using the 5-hydroxy-3-(4-methylthiophenoxy)benzoicacid methyl ester obtained in Production Example 1,2-bromopropionic acidtert-butyl ester and 3-amino-1-methyl-1H-pyrazole, by the same method asin Production Example 1, a corresponding method, or a combinationthereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.44(9H,s), 1.60(3H,d,J=6.8 Hz), 3.07(3H,s), 3.81(3H,s),4.69(1H,q,J=6.8 Hz), 6.77(1H,br), 7.10-7.16(3H,m), 7.24(1H,br),7.29(1H,d,J=2.2 Hz), 7.92(2H,d,J=8.9 Hz), 8.38(1H,br)

ESI-MS(m/e): 516[M+H]⁺

PRODUCTION EXAMPLE 140

Preparation of3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-methoxy-1-methyl-ethoxy)-N-(pyrazol-3-yl)-benzamide

The compound of Production Example 140 was obtained as a colorlessamorphous substance using 5-hydroxy-3-methoxymethoxybenzoic acid methylester, 5-bromo-2-ethanesulfonylpyridine, (2R)-2-hydroxy-1-methoxypropaneand 3-amino-pyrazole, by the same method as in Production Example 117, acorresponding method, or a combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.33(t,3H,J=7.3 Hz), 1.34(d,3H,J=6.2 Hz), 3.40(q,2H,J=7.3Hz), 3.41(s,3H), 3.52-3.62(m,2H), 4.60-4.65(m,1H,J=6.2 Hz,-Hz),6.83(d,1H,J=2.2 Hz), 6.86(s,1H), 7.20(s,1H), 7.42(d,1H,J=2.2 Hz),7.42(dd,1H,J=8.8,2.6 Hz), 7.49(s,1H), 7.04(d,1H,J=8.8 Hz),8.47(d,1H,J=2.6 Hz), 9.47(brs,1H)

ESI-MS(m/e): 461[M+H]⁺,459[M−H]⁻

PRODUCTION EXAMPLE 141

Preparation of3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)-5-(tetrahydrofuran-3-yl)benzamide

The compound of Production Example 141 was obtained as a colorless oilusing 5-hydroxy-3-methoxymethoxybenzoic acid methyl ester,5-bromo-2-methanesulfonylpyridine, (S)-(+)-3-hydroxytetrahydrofuran and3-amino-1-methyl-1H-pyrazole, by the same method as in ProductionExample 117, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 2.15-2.26(m,1H), 2.26-2.30(m,1H), 3.24(s,3H), 3.80(s,3H),3.88-4.03(m,4H), 4.97(m,1H), 6.76(m,2H), 7.11(t,1H,J=2.2 Hz),7.24(d,1H,J=2.2 Hz)7.28(d,1H,J=2.2 Hz), 7.44(dd,1H,J=2.9,8.4 Hz),8.05(d,1H,J=8.4 Hz), 8.44(br,1H), 8.45(d,1H,J=2.9 Hz)

ESI-MS(m/e): 459[M+H]⁺

PRODUCTION EXAMPLE 142

Preparation ofN-(1-ethyl-1H-pyrazol-3-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)benzamide

The compound of Production Example 142 was obtained as a white amorphoussubstance using 5-hydroxy-3-methoxymethoxybenzoic acid methyl ester,5-bromo-2-methanesulfonylpyridine,(2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and3-amino-1-ethyl-1H-pyrazole, by the same method as in Production Example117, a corresponding method, or a combination thereof with an ordinarymethod.

¹HNMR(CDCl₃)δ: 1.33(d,3H,J=6.2 Hz), 1.47(t,3H,J=7.3 Hz), 1.98(m,1H),3.24(s,3H)3.77(m,2H) 4.07(q,2H,J=7.3 Hz), 4.58(m,1H), 6.77(d,1H,J=2.6Hz), 6.82(t,1H,J=2.6 Hz), 7.13(m,1H), 7.32(m,2H), 7.45(dd,1H,J=2.6,8.4Hz), 8.06(d,1H,J=8.4 Hz), 8.34(br,1H), 8.47(d,1H,J=2.6 Hz)

ESI-MS(n/e): 461[M+H]⁺

PRODUCTION EXAMPLE 143

Preparation of5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(pyrazol-3-yl)benzamide

The compound of Production Example 143 was obtained as a white amorphoussubstance using 5-hydroxy-3-methoxymethoxybenzoic acid methyl ester,5-bromo-2-methanesulfonylpyridine, 1,3-difluoro-2-propanol and3-amino-pyrazole, by the same method as in Production Example 117, acorresponding method, or a combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 3.23(s,3H), 4.55-4.70(m,2H), 4.70-4.90(m,3H), 6.79(m,1H),6.91(m,1H), 7.28(m,1H), 7.42-7.51(m,3H), 8.04(d,1H,J=8.9 Hz),8.44(d,1H,J=2.6 Hz), 9.60(br,1H)

ESI-MS(m/e): 453[M+H]⁺

PRODUCTION EXAMPLE 144

Preparation of3-(6-methanesulfonylpyridin-3-yloxy)-5-(2-methoxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

The compound of Production Example 144 was obtained as a colorless oilusing 5-hydroxy-3-methoxymethoxybenzoic acid methyl ester,5-bromo-2-methanesulfonylpyridine, (2R)-2-hydroxy-1-methoxypropane and3-amino-1-methyl-1H-pyrazole, by the same method as in ProductionExample 117, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 1.32(d,3H,J=6.4 Hz), 3.23(s,3H), 3.40(s,3H), 3.54(m,2H),3.78(s,3H), 4.59(m,1H), 6.78(m,1H), 6.84(m,1H), 7.14(m,1H), 7.29(m,1H),7.32(m,1H), 7.44(dd,1H,J=2.6,8.6 Hz), 8.05(d,1H,J=8.6 Hz),8.47(d,1H,J=2.6 Hz), 8.66(br,1H)

ESI-MS(m/e): 461 [M+H]⁺

PRODUCTION EXAMPLE 145

Preparation of3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-fluoro-1-fluoromethyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

The compound of Production Example 145 was obtained as a colorlessamorphous substance using 5-hydroxy-3-methoxymethoxybenzoic acid methylester, 5-bromo-2-ethanesulfonylpyridine, 1,3-difluoro-2-propanol and3-amino-1-methyl-1H-pyrazole, by the same method as in ProductionExample 117, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 1.33(t,3H,J=7.42 Hz), 3.41 (q,2H,J=7.4 Hz), 3.80(s,3H),4.61-4.65(m,2H), 4.73-4.78(m,3H), 6.78(dd,1H,J=2.0,1.8 Hz),6.91(d,1H,J=2.3 Hz), 7.23(dd,1H,J=1.8,1.6 Hz), 7.30(d,1H,J=2.3 Hz),7.38(dd,1H,J=2.0,1.6 Hz), 7.16(dd,1H,J=8.6,2.7 Hz), 8.08(d,1H,J=8.6 Hz),8.50(d,1H,J=2.7 Hz), 8.63(brs,1H)

ESI-MS(m/e): 481[M+H]⁺,479[M−H]⁻

PRODUCTION EXAMPLE 146

Preparation of2-[3-(4-methanesulfonylphenoxy)-5-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-phenoxy]propionicacid

The compound of Production Example 146 was obtained as a white solid byconversion of the tert-butyl ester portion of the2-[3-(4-methanesulfonylphenoxy)-5-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-phenoxy]propionicacid-tert-butyl ester obtained in Production Example 139 to a carboxylgroup. The conversion of the ester portion to a carboxyl group wasaccomplished by the method described in Comprehensive OrganicTransformations, Richard L. et al., VCH Publishers, 1988, acorresponding method, or a combination thereof with an ordinary method.

¹HNMR(CH₃OD)δ: 1.60(3H,d,J=6.8 Hz), 3.11(3H,s), 3.82(3H,s),6.54-6.58(1H,br), 6.84(1H,br), 7.16-7.28(3H,m), 7.34(1H,br),7.49(1H,d,J=2.1 Hz), 7.95(2H,d,J=8.9 Hz)

ESI-MS(m/e): 460[M+H]⁺

PRODUCTION EXAMPLE 147

Preparation of3-(6-ethanesulfonylpyridin-3-yloxy)-5-isopropoxy-N-(pyrazol-3-yl)benzamide

The compound of Production Example 147 was obtained as a colorlessamorphous substance using 5-hydroxy-3-methoxymethoxybenzoic acid methylester, 5-bromo-2-ethanesulfonylpyridine, 2-hydroxypropane and3-amino-pyrazole, by the same method as in Production Example 117, acorresponding method, or a combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.32(t,3H,J=7.3 Hz), 1.37(d,6H,J=5.9 Hz), 3.39(q,2H,J=7.3Hz)m 4.60(septet,1H,J=5.9 Hz), 6.76(dd,1H,J=2.2,2.2 Hz), 6.84(s,1H),7.16(s,1H), 7.33(s,1H), 7.40(dd,1H,J=8.8,2.6 Hz), 7.51(dd,1H,J=2.2,2.6Hz), 8.03(dd,1H,J=8.8,2.6 Hz), 8.46(dd,1H,J=2.6,2.6 Hz), 9.03(brs,1H)

ESI-MS(m/e): 431[M+H]⁺,429[M−H]⁻

PRODUCTION EXAMPLE 148

Preparation of3-(6-ethanesulfonylpyridin-3-yloxy)-5-isopropoxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide

The compound of Production Example 148 was obtained as a colorlessamorphous substance using 5-hydroxy-3-methoxymethoxybenzoic acid methylester, 5-bromo-2-ethanesulfonylpyridine, 2-hydroxypropane and3-amino-1-methyl-1H-pyrazole, by the same method as in ProductionExample 117, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 1.34(t,3H,J=7.3 Hz), 1.37(d,6H,J=5.9 Hz), 3.41(q,2H,J=7.3 Hz), 3.81(s,3H), 4.60(septet,1H,J=5.9 Hz), 6.75-6.78(m,2H),7.11(s,1H), 7.26(s,1H), 7.28(d,1H,J=2.2 Hz), 7.42(dd,1H,J=8.8,2.9 Hz),8.05(d,1H,J=8.8 Hz), 8.36(brs,1H), 8.48(d,1H,J=2.9 Hz)

ESI-MS(m/e): 445[M+H]⁺,443[M−H]⁻

PRODUCTION EXAMPLE 149

Preparation of3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(pyrazol-3-yl)benzamide

The compound of Production Example 149 was obtained as a colorlessamorphous substance using 5-hydroxy-3-methoxymethoxybenzoic acid methylester, 5-bromo-2-ethanesulfonylpyridine,(2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 3-amino-pyrazole,by the same method as in Production Example 117, a corresponding method,or a combination thereof with an ordinary method.

¹HNMR(CDCl₃ (one drop of CH₃OD))δ: 1.29(d,3H,J=6.3 Hz), 1.31 (t,3H,J=7.4Hz), 3.39(q,2H,J=7.4 Hz), 3.70-3.76(m,2H), 4.55(septet,1H,J=6.3 Hz),6.77(s,1H), 6.79(d,1H,J=2.3 Hz), 7.20(s,1H), 7.37(s,1H),7.41(dd,1H,J=8.6,2.7 Hz), 7.49(d,1H,J=2.3 Hz), 8.02(d,1H,J=8.6 Hz),8.44(d,1H,J=2.7 Hz), 9.55(brs,1H)

ESI-MS(m/e): 447[M+H]⁺,445[M−H]⁻

PRODUCTION EXAMPLE 150

Preparation of3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(pyridin-2-yl)benzamide

The compound of Production Example 150 was obtained as a colorlessamorphous substance using 5-hydroxy-3-methoxymethoxybenzoic acid methylester, 5-bromo-2-ethanesulfonylpyridine,(2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 2-aminopyridine,by the same method as in Production Example 117, a corresponding method,or a combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.33(d,3H,J=6.1 Hz), 1.33(t,3H,J=7.4 Hz), 3.41(q,2H,J=7.4Hz), 3.78-3.80(m,2H), 4.62(dq,1H,J=4.5,6.1 Hz), 6.84(s,1H),7.11(dd,1H,J=6.6,5.1 Hz), 7.22(s,1H), 7.38(s,1H), 7.45(dd,1H,J=8.8,2.5Hz), 7.78(dd,1H,J=8.4,6.6 Hz), 8.08(d,1H,J=8.8 Hz), 8.30(d,1H,J=5.1 Hz),8.34(d,1H,J=8.4 Hz), 8.50(d,1H,J=2.5 Hz), 8.63(brs,1H)

ESI-MS(m/e): 481[M+H]⁺

PRODUCTION EXAMPLE 151

Preparation of3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide

The compound of Production Example 151 was obtained as a colorlessamorphous substance using 5-hydroxy-3-methoxymethoxybenzoic acid methylester, 5-bromo-2-ethanesulfonylpyridine,(2R)-1-(tert-butyldimethylsiloxy)-2-hydroxypropane and 2-aminothiazole,by the same method as in Production Example 117, a corresponding method,or a combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.31(d,3H,J=6.3 Hz), 1.33(t,3H,J=7.4 Hz), 3.41(q,2H,J=7.4Hz), 3.76-3.78(m,2H), 4.55-4.60(m,1H), 6.86(m,1H), 7.02(d,1H,J=3.5 Hz),7.26(m,1H), 7.29(d,1H,J=3.5 Hz), 7.42(m,1H), 7.46(dd,1H,J=8.6,2.7 Hz),8.08(d,1H,J=8.6 Hz), 8.49(d,1H,J=2.7 Hz)

ESI-MS(m/e): 464[M+H]⁺,462[M−H]⁻

PRODUCTION EXAMPLE 152

Preparation of5-(2-fluoro-1-methyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

The compound of Production Example 152 was obtained as a colorlessamorphous substance by conversion of the hydroxyl group of the5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamideobtained in Production Example 126 to mesylate with triethylamine andmethanesulfonyl chloride, followed by reaction with tetrabutylammoniumchloride.

¹HNMR(CDCl₃)δ: 1.35(dd,3H,J=1.6,6.2 Hz), 3.24(s,3H), 3.77(s,3H),4.45(m,1H), 4.57(m,1H), 4.67(m,1H), 6.79(d,1H,J=2.3 Hz), 6.84(t,1H,J=2.3Hz), 7.16(t,1H,J=2.3 Hz), 7.30(d,1H,J2.3 Hz), 7.32(m,1H),7.45(d,1H,J=2.3,8.6 Hz), 8.06(d,1H,J=8.6 Hz), 8.47(d,1H,J=2.3 Hz),8.79(br,1H)

ESI-MS(M/E):449[M+H]⁺

PRODUCTION EXAMPLE 153

Preparation of5-(2-chloro-1-methyl-ethoxy)-3-(6-ethanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

The compound of Production Example 153 was obtained as a colorlessamorphous substance during conversion of the hydroxyl group of the3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamideobtained in Production Example 117 to mesylate with triethylamine andmethanesulfonyl chloride.

¹HNMR(CDCl₃)δ: 1.33(t,3H,J=7.4 Hz), 1.45(d,3H,J=6.2 Hz), 3.41(q,2H,J=7.4Hz) 3.63(dd,1H,J=5.0,11.5 Hz), 3.69(dd,1H,J=5.0,11.5 Hz), 3.79(s,3H),4.62(m,1H), 6.79(d,1H,J=2.2 Hz), 6.83(t,1H,J=2.2 Hz), 7.18(m,1H),7.29-7.35(m,2H), 7.45(dd,1H,J=2.7,8.6 Hz), 8.07(d,1H,J=8.6 Hz),8.49(d,1H,J=2.7 Hz), 8.67(br,1H)

ESI-MS(M/E):479[M+H]⁺

PRODUCTION EXAMPLE 154

Preparation of5-(2-fluoro-1-fluoromethyl-ethoxy)-N-(isoxazol-3-yl)-3-(6-methanesulfonylpyridin-3-yloxy)benzamide

The compound of Production Example 154 was obtained as a white amorphoussubstance using 5-hydroxy-3-methoxymethoxybenzoic acid methyl ester,5-bromo-2-methanesulfonylpyridine, 1,3-difluoro-2-propanol and3-aminooxazole, by the same method as in Production Example 117, acorresponding method, or a combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 3.24(s,3H), 4.59-4.70(m,2H), 4.70-4.90(m,3H),6.96(t,1H,J=2.3 Hz), 7.19(m,1H), 7.32(m,1H), 7.45(m,1H),7.48(dd,1H,J=2.7,8.5 Hz), 8.09(d,1H,J=8.5 Hz), 8.29(m,1H),8.49(d,1H,J=2.7 Hz), 9.60(br,1H)

ESI-MS(M/E):454[M+H]⁺

PRODUCTION EXAMPLE 155

Preparation of5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(pyridin-2-yl)benzamide

The compound of Production Example 155 was obtained as a white amorphoussubstance using 5-hydroxy-3-methoxymethoxybenzoic acid methyl ester,5-bromo-2-methanesulfonylpyridine, 1,3-difluoro-2-propanol and2-aminopyridine, by the same method as in Production Example 117, acorresponding method, or a combination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 3.24(s,3H), 4.60-4.70(m,2H), 4.70-4.90(m,3H),6.93(t,1H,J=2.1 Hz), 7.10(m,1H), 7.26(m,1H), 7.42(m1H),7.48(dd,1H,J=2.1,8.2 Hz), 7.78(dt,1H,J=), 8.09(d,1H,J=8.4 Hz),8.30(m,1H), 8.32(d,1H,J=8.4 Hz), 8.49(d,1H,J=2.1 Hz), 8.59(br,1H)

ESI-MS(M/E):464[M+H]⁺

PRODUCTION EXAMPLE 156

Preparation of5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(3-methyl-[1,2,4]-thiadiazol-5-yl)benzamide

The compound of Production Example 156 was obtained as a white amorphoussubstance using 5-hydroxy-3-methoxymethoxybenzoic acid methyl ester,5-bromo-2-methanesulfonylpyridine, 1,3-difluoro-2-propanol and5-amino-3-methyl-[1,2,4]thiadiazole, by the same method as in ProductionExample 117, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 2.50(s,3H), 3.27(s,3H), 4.57-4.67(m,2H), 4.67-4.90(m,3H),7.01(t,1H,J=2.3 Hz), 7.29(m,1H), 7.45(m,1H), 7.49(dd,1H,J=2.3,8.7 Hz),8.09(d,1H,J=8.7 Hz), 8.47(d,1H,J=2.3 Hz)

ESI-MS(M/E):485[M+H]⁺

PRODUCTION EXAMPLE 157

Preparation of3-(4-dimethylsulfamoylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

The compound of Production Example 157 was obtained as a white amorphoussubstance using 5-hydroxy-3-methoxymethoxybenzoic acid methyl ester,4-bromo-dimethylsulfamoylbenzene,(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and3-amino-1-methyl-1H-pyrazole, by the same method as in ProductionExample 42, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 1.31(d,3H,J=6.3 Hz), 2.19(brs,1H), 2.74(s,6H),3.76-3.80(m,2H), 3.81(s,3H), 4.54-4.59(m,1H,J=6.3 Hz,-Hz), 6.79(m,1H),6.81(m,1H), 7.11(d,2H,J=9.0 Hz), 7.13(s,1H), 7.29-7.30(m,2H),7.77(d,2H,J=9.0 Hz), 8.55(br,1H)

ESI-MS(m/e): 475[M+H]⁺, 473[M−H]⁻

PRODUCTION EXAMPLE 158

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-3-(3-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

The compound of Production Example 158 was obtained as a white amorphoussubstance using 5-hydroxy-3-methoxymethoxybenzoic acid methyl ester,3-methylthio-phenylboric acid,(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and3-amino-1-methyl-1H-pyrazole, by the same method as in ProductionExample 1 or Production Example 89, a corresponding method, or acombination thereof with an ordinary method.

¹HNMR(CDCl₃)δ: 1.30(d,3H,J=6.2 Hz), 2.08(t,1H,J=6.5 Hz), 3.07(s,3H),3.73-3.78(m,5H), 4.52-4.57(m,1H), 6.77-6.78(m,2H), 7.08(d,1H,J=2.1 Hz),7.25-7.31(m,3H), 7.54(t,1H,J=7.6 Hz), 7.59(d,1H,J=2.1 Hz),7.70(d,1H,J=7.6 Hz), 8.49(brs,1H)

ESI-MS(m/e): 446[M+H]⁺

PRODUCTION EXAMPLE 159

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-3-(6-isopropylsulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

The compound of Production Example 159 was obtained as a white amorphoussubstance using 5-hydroxy-3-methoxymethoxybenzoic acid methyl ester,5-bromo-2-isopropylsulfonylpyridine,(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and3-amino-1-methyl-1H-pyrazole, by the same method as in ProductionExample 117, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 1.31(d,3H,J=5.9 Hz), 1.35(d,6H,J=6.7 Hz), 2.25(brs,1H),3.72(septet,1H,J=6.7 Hz), 3.70-3.81(m,2H), 3.81(s,3H), 4.53-4.59(m,1H),6.78-6.79(m,1H), 6.80-6.82(m,1H), 7.17(m,1H), 7.29-7.31(m,1H),7.32(m,1H), 7.43(dd,1H,J=8.6,2.7 Hz), 8.06(d,1H,J=8.6 Hz),8.50(d,1H,J=2.7 Hz), 8.60(brs,1H)

ESI-MS(m/e): 475[M+H]⁺, 473[M−H]⁻

PRODUCTION EXAMPLE 160

Preparation of3-(3-chloro-4-methanesulfonylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

The compound of Production Example 160 was obtained as a white amorphoussubstance using 5-hydroxy-3-methoxymethoxybenzoic acid methyl ester,4-bromo-2-chloro-methanesulfonylbenzene,(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and3-amino-1-methyl-1H-pyrazole, by the same method as in ProductionExample 42, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 1.31(d,3H,J=6.1 Hz), 3.28(s,3H), 3.76-3.80(m,5H),4.54-4.59(m,1H), 6.80-6.81(m,2H), 7.02(dd,1H,J=2.3,8.8 Hz),7.14-7.15(m,2H), 7.30(d,1H,J=2.3 Hz), 7.33(s,1H), 8.11(d,1H,J=8.8 Hz),8.75(brs,1H)

ESI-MS(n/e): 480[M+H]⁺

PRODUCTION EXAMPLE 161

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-3-(pyridin-3-yloxy)benzamide

The compound of Production Example 161 was obtained as a white amorphoussubstance using 5-hydroxy-3-methoxymethoxybenzoic acid methyl ester,3-iodopyridine, (2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and3-amino-1-methyl-1H-pyrazole, by the same method as in ProductionExample 117, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 1.30(d,3H,J=6.3 Hz), 2.27(br,1H), 3.72-3.80(m,2H),3.80(s,3H), 4.55(m,1H), 6.75(t,1H,J=2.3 Hz), 6.79(d,1H,J=2.3 Hz),7.05(m,1H), 7.22(m,1H), 7.29(d,1H,J=2.3 Hz), 7.31-7.38(m,2H),8.44(m,2H), 8.62(br,1H)

ESI-MS(M/E): 369[M+H]⁺

PRODUCTION EXAMPLE 162

Preparation of5-(2-fluoro-1-fluoromethyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-3-(pyridin-3-yloxy)benzamide

The compound of Production Example 162 was obtained as a white amorphoussubstance using 5-hydroxy-3-methoxymethoxybenzoic acid methyl ester,3-iodopyridine, 1,3-difluoro-2-propanol and3-amino-1-methyl-1H-pyrazole, by the same method as in ProductionExample 117, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 3.77(s,3H), 4.55-4.67(m,2H), 4.67(m,3H), 6.79(d,1H,J=2.3Hz), 6.82(t,1H,J=2.3 Hz), 7.11(m,1H), 7.26(m,1H), 7.29(d,1H,J=2.3 Hz),7.30-7.38(m,2H), 8.45(m,2H), 8.70(br,1H)

ESI-MS(M/E): 389[M+H]⁺

PRODUCTION EXAMPLE 163

Preparation of5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-3-(pyridin-4-yloxy)benzamide

The compound of Production Example 163 was obtained as a white amorphoussubstance using 5-hydroxy-3-methoxymethoxybenzoic acid methyl ester,4-chloropyridine hydrochloride,(2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and3-amino-1-methyl-1H-pyrazole, by the same method as in ProductionExample 117, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 1.31(d,3H,J=6.3 Hz), 2.05(br,1H), 3.77(m,2H), 3.82(s,3H),4.56(m,1H), 6.79(d,1H,J=2.3 Hz), 6.83(t,1H,J=2.3 Hz),6.88(dd,2H,J=1.6,4.7 Hz), 7.15(m,1H), 7.30(d,1H,J=2.2 Hz), 7.33(m,1H),8.42(br,1H), 8.51(dd,2H,J=1.6,4.7 Hz)

ESI-MS(M/E): 369[M+H]⁺

PRODUCTION EXAMPLE 164

Preparation of5-(2-fluoro-1-fluoromethyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-3-(pyridin-4-yloxy)benzamide

The compound of Production Example 164 was obtained as a white amorphoussubstance using 5-hydroxy-3-methoxymethoxybenzoic acid methyl ester,4-chloropyridine hydrochloride, 1,3-difluoro-2-propanol and3-amino-1-methyl-1H-pyrazole, by the same method as in ProductionExample 117, a corresponding method, or a combination thereof with anordinary method.

¹HNMR(CDCl₃)δ: 3.81(s,3H), 4.58-4.67(m,2H), 4.67-4.82(m,3H),6.79(d,1H,J=2.0 Hz), 6.89(dd,2H,J=1.6,4.7 Hz), 6.91(t,1H,J2.3 Hz),7.21(t,1H,J=2.3 Hz), 7.30(d,1H,J=2.0 Hz), 7.38(t,1H,J=2.3 Hz),8.52(br,1H), 8.52(dd,2H,J=1.6,4.7 Hz)

ESI-MS(M/E): 389[M+H]⁺

PRODUCTION EXAMPLE 165

Preparation of2-[3-(6-ethanesulfonylpyridin-3-yloxy)-5-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-phenoxy]propionicacid

The compound of Production Example 165 was obtained as a white solid byconversion of the tert-butyl ester portion of2-[3-(6-ethanesulfonylpyridin-3-yloxy)-5-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-phenoxy]propionicacid-tert-butyl ester obtained in the same manner as Production Example1 to a carboxyl group, using the3-(6-ethanesulfonylpyridin-3-yloxy)-5-hydroxy-benzoic acid methyl esterobtained in Production Example 117, 2-bromopropionic acid tert-butylester and 3-amino-1-methyl-1H-pyrazole. The conversion of the esterportion to a carboxyl group was accomplished by the method described inComprehensive Organic Transformations, Richard L. et al., VCHPublishers, 1988, a corresponding method, or a combination thereof withan ordinary method.

¹HNMR(CDCl₃)δ: 1.24(3H,t,J=7.4 Hz), 1.59(3H,d,J=6.8 Hz), 3.39(2H,q,J=7.4Hz), 3.81(3H,s), 4.69-4.80(1H,m), 6.56(1H,d,J=2.3 Hz), 6.90(1H,t,J=2.2Hz), 7.25(1H,br), 7.37(1H,br), 7.48(1H,d,J=2.3 Hz), 7.62(1H,dd,J=8.7Hz,2.7 Hz), 8.07(1H,d,J=6.4 Hz), 8.52(1H,d,J=2.7 Hz)

ESI-MS(M/E): 475[M+H]⁺

PRODUCTION EXAMPLE 166

Preparation of5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(3-fluoro-4-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

The compound of Production Example 166 was obtained as a colorlessamorphous substance using3-(3-fluoro-4-methanesulfonylphenoxy)-5-hydroxy-benzoic acid methylester, 1,3-difluoro-2-propanol and 3-amino-1-methyl-1H-pyrazole obtainedin the same manner as Production Example 42, by the same method as inProduction Example 2, a corresponding method, or a combination thereofwith an ordinary method.

¹HNMR(CDCl₃)δ: 3.23(3H,s), 3.82(3H,s), 4.61-4.78(5H,m), 6.78(1H,d,J=2.3Hz), 6.83-6.94(3H,m), 7.19(1H,t,J=1.8 Hz), 7.30(1H,d,J=2.3 Hz),7.38(1H,t,J=1.8 Hz), 7.94(1H,t,J=8.4 Hz), 8.37(1H,brs)

ESI-MS(M/E): 484[M+H]⁺

INDUSTRIAL APPLICABILITY

The heteroarylcarbamoylbenzene derivatives of the present inventionrepresented by formula (I) exhibit excellent glucokinase activity, andare therefore useful for treatment and/or prevention of diabetes,diabetes complications or obesity in the field of medicine.

1. A compound represented by formula (I):

or a pharmaceutically acceptable salt or solvate thereof, wherein: X¹represents oxygen, sulfur or NH; X² represents oxygen, sulfur or CH₂; R¹represents 1 or 2 substituents optionally present on Ring A which areselected from the group consisting of: alkylsulfonyl, alkanoyl, loweralkyl, hydroxyalkyl, hydroxy, alkylcarbamoyl, alkylsulfamoyl,dialkylsulfamoyl, alkylthio, alkoxy, dialkylcarbamoyl,alkoxycarbonylamino, alkoxycarbonyl, halogen atoms, alkanoylaminoalkyl,alkoxycarbonylaminoalkyl, alkylsulfonylaminoalkyl, cyano andtrifluoromethyl; R² represents: a C3-7 cyclic alkyl group wherein one ofthe constituent carbon atoms of the ring, except for the carbon atom,which is bonded to X², is optionally replaced with oxygen, NH,N-alkanoyl or CONH; a straight-chain or branched lower alkyl group or alower alkenyl group, optionally having a substituent selected from thegroup consisting of halogen atoms, carboxyl, alkoxycarbonyl, hydroxy,amino optionally substituted with 1 or 2 alkanoyl or lower alkyl groups,alkoxy and N-alkylcarbamoyl; R³ represents 1 or 2 substituentsoptionally present on Ring B which are selected from the groupconsisting of: lower alkyl; alkoxy; alkylamino; lower dialkylamino;halo; trifluoromethyl; hydroxyalkyl, wherein the hydrogen of the hydroxyin the hydroxyalkyl group may be substituted with lower alkyl;aminoalkyl; alkanoyl; carboxyl; alkoxycarbonyl and cyano; the followingformula (II):

represents a 6- to 10-membered aryl group or 5- to 7-membered heteroarylgroup optionally having on the ring 1 or 2 substituents represented byR¹ above, and formula (III):

represents a monocyclic or bicyclic heteroaryl group optionally having 1or 2 substituents represented by R³ above, wherein the carbon atom ofRing B that is bonded to the nitrogen atom of the amide group of formula(I) forms a C═N bond with the nitrogen atom of the ring.
 2. A compoundaccording to claim 1 wherein X¹ is O or S, and X²is O or CH₂.
 3. Acompound according to claim 2 wherein Ring A is phenyl or a 5- to6-membered heteroaryl group.
 4. A compound according to claim 2 whereinRing A is phenyl.
 5. A compound according to claim 2 wherein Ring A is a5- to 6-membered heteroaryl group.
 6. A compound according to claim 4wherein R¹ is alkylsulfonyl, alkanoyl, hydroxyalkyl, alkylcarbamoyl,alkylsulfamoyl, dialkylsulfamoyl, dialkylcarbamoyl, alkoxycarbonylamino,halogen atoms, alkanoylaminoalkyl, alkylsulfonylaminoalkyl oralkoxycarbonylaminoalkyl. 7-32. (canceled)
 33. A compound according toclaim 5 wherein R¹ is alkylsulfonyl, alkanoyl, hydroxyalkyl,alkylcarbamoyl, alkylsulfamoyl, dialkylsulfamoyl, dialkylcarbamoyl,alkoxycarbonylamino, halogen atoms, alkanoylaminoalkyl,alkylsulfonylaminoalkyl or alkoxycarbonylaminoalkyl.
 34. A compoundaccording to claim 4 wherein R¹ is alkylsulfonyl, alkanoyl,hydroxyalkyl, alkanoylaminoalkyl, alkylsulfonylaminoalkyl oralkoxycarbonylaminoalkyl.
 35. A compound according to claim 34 whereinR¹ is alkylsulfonyl, alkanoyl or hydroxyalkyl.
 36. A compound accordingto claim 3 wherein formula (III) represents a monocyclic or bicyclicheteroaryl group, provided that the heteroaryl group is not5-alkoxycarbonyl-pyridin-2-yl or 5-carboxyl-pyridin-2-yl, saidheteroaryl group being optionally substituted with 1 or 2 substituentsrepresented by R³.
 37. A compound according to claim 34 wherein Ring Bcontains at least one hetero atom in the ring in addition to thenitrogen atom forming the C═N group, said heteroatom being selected fromthe group consisting of nitrogen, sulfur and oxygen.
 38. A compoundaccording to claim 1 wherein R² is a C3-7 cyclic alkyl group in whichone of the carbon atoms of the ring is optionally replaced with oxygen,NH or N-alkanoyl, or a straight-chain or branched lower alkyl group or alower alkenyl group, optionally substituted with a halo, carboxyl,alkoxycarbonyl, hydroxy, amino optionally substituted with 1 or 2 loweralkyl groups, alkoxy, N-alkylcarbamoyl or alkanoylamino.
 39. A compoundaccording to claim 1, wherein Ring B is selected from the groupconsisting of: thiazolyl, imidazolyl, isothiazolyl, thiadiazolyl,triazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyrazolyl,pyrimidinyl, pyridothiazolyl and benzothiazolyl.
 40. A compoundaccording to claim 1 wherein R³ is lower alkyl; alkoxy; halo;hydroxyalkyl in which the hydrogen of the hydroxy in the hydroxyalkylgroup may be substituted with lower alkyl; aminoalkyl or alkanoyl.
 41. Acompound according to claim 1 wherein R³ is lower alkyl or hydroxyalkylin which the hydrogen of the hydroxy in the hydroxyalkyl group may besubstituted with lower alkyl.
 42. A compound in accordance with claim 1,selected from the group consisting of:5-isopropoxy-3-(4-methanesulfonylphenoxy)-N-(4-methylthiazol-2-yl)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,5-ethoxy-3-(4-methanesulfonylphenoxy)-N-(4-methoxymethyl-thiazol-2-yl)benzamide,5-cyclopentyloxy-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,3-(4-methanesulfonylphenoxy)-5-(tetrahydrofuran-3-yloxy)-N-thiazol-2-yl-benzamide,3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide,3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methoxymethyl-ethoxy)-N-thiazol-2-yl-benzamide,3-(2-fluoro-4-methanesulfonylphenoxy)-5-isopropoxy-N-thiazol-2-yl-benzamide,3-(4-methanesulfonylphenoxy)-5-(1-methoxymethyl-propoxy)-N-(4-methyl-thiazol-2-yl)-benzamide,5-isopropoxy-3-(4-methanesulfonylphenoxy)-N-pyrazol-3-yl-benzamide,5-isopropoxy-3-(4-methanesulfonylphenoxy)-N-pyrazin-2-yl-benzamide,3-(4-methanesulfonylphenoxy)-5-(3-methoxy-1-methyl-propoxy)-N-thiazol-2-yl-benzamide,5-(3-hydroxy-1-methyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(4-methanesulfonylphenoxy)-N-pyrimidin-4-yl-benzamide,5-isopropoxy-3-(4-methanesulfonylphenoxy)-N-(pyrimidin-2-yl)-benzamide,N-(4-hydroxymethyl-thiazol-2-yl)-5-isopropoxy-3-(4-methanesulfonylphenoxy)-benzamide,N-(isooxazol-3-yl)-3-(4-methanesulfonylphenoxy)-5-(1-methoxymethyl-propoxy)-benzamide,3-(4-methanesulfonylphenoxy)-5-(1-methoxymethyl-propoxy)-N-[1,3,4]thiadiazol-2-yl-benzamide,5-(1-hydroxymethyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-(4-methyl-thiazol-2-yl)-benzamide,N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methanesulfonylphenoxy)-5-(1-methoxymethyl-propoxy)-benzamide,5-(2-amino-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,5-(2-dimethylamino-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-propoxy)-3-(4-methanesulfonylphenoxy)-N-(4-methyl-thiazol-2-yl)-benzamide,3-(4-methanesulfonylphenoxy)-5-(2-methoxy-propoxy)-N-(4-methyl-thiazol-2-yl)-benzamide,5-isopropoxy-3-(4-methanesulfonylphenoxy)-N-(thiazolo[5,4-b]pyridin-2-yl)-benzamide,5-(2-hydroxymethyl-allyl)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazolo[5,4-b]pyridin-2-yl-benzamide,5-(3-hydroxy-2-methyl-propyl)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,3-(4-methanesulfonylphenoxy)-N-(4-methyl-thiazol-2-yl)-5-(piperidin-4-yl-oxy)-benzamidehydrochloride,5-(1-acetyl-piperidin-4-yloxy)-3-(4-methanesulfonylphenoxy)-N-(4-methyl-thiazol-2-yl)-benzamide,2-[3-(4-methanesulfonylphenoxy)-5-(4-methyl-thiazol-2-yl-carbamoyl)-phenoxy]propionicacid,5-(3-hydroxy-1-methyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,3-(4-methanesulfonylphenoxy)-5-(1-methylcarbamoyl-ethoxy)-N-(4-methyl-thiazol-2-yl)-benzamide,5-(2-acetylamino-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-5-isopropoxy-3-(4-methanesulfonylphenoxy)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-pyridin-2-yl-benzamide,5-(2-hydroxy-ethoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-cyclopentyloxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,N-(4-acetyl-thiazol-2-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methanesulfonylphenoxy)-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-benzamide,3-(3-fluoro-4-methanesulfonylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(5-methyl-thiazol-2-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-([1,2,4]thiadiazol-5-yl)-benzamide,N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(5-methoxycarbonyl-pyridin-2-yl)-benzamide,6-[5-isopropoxy-3-(4-methanesulfonylphenoxy)-benzoylamino]nicotinicacid,5-(2-hydroxy-1-methyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)-3-(4-methanesulfonylphenoxy)-benzamide,N-(5-hydroxymethyl-thiazol-2-yl)-5-isopropoxy-3-(4-methanesulfonylphenoxy)-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-benzamide,N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methanesulfonylphenoxy)-5-(tetrahydrofuran-3-yl-oxy)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(2-methylthiazol-4-yl)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(4-methoxymethyl-thiazol-2-yl)-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-3-(4-methanesulfonylphenoxy)-5-(tetrahydrofuran-3-yl-oxy)-benzamide,N-[4-(1-hydroxy-ethyl)-thiazol-2-yl]-3-(4-methanesulfonylphenoxy)-5-(tetrahydrofuran-3-yl-oxy)-benzamide,N-(2,5-dimethylthiazol-4-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-benzamide,5-isopropoxy-3-(4-methoxycarbonylaminomethylphenoxy)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(4-methylcarbamoyl-phenoxy)-N-thiazol-2-yl-benzamide,3-(4-dimethylcarbamoyl-phenoxy)-5-isopropoxy-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(4-methylcarbonylaminomethyl-phenoxy)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(4-methanesulfonylaminomethyl-phenoxy)-N-thiazol-2-yl-benzamide,3-[4-(1-hydroxy-propyl)-phenoxy]-5-isopropoxy-N-thiazol-2-yl-benzamide,6-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl)-phenoxy]-nicotinic acid methylester,3-(5-hydroxymethyl-pyridin-2-yl-oxy)-5-isopropoxy-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(5-methanesulfonylpyridin-2-yl)-N-thiazol-2-yl-benzamide,3-(5-acetyl-pyridin-2-yl-oxy)-5-isopropoxy-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(5-methoxycarbonyl-pyrazin-2-yl-oxy)-N-thiazol-2-yl-benzamide,3-(5-cyano-pyridin-2-yl-oxy)-5-isopropoxy-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridin-4-yl-oxy)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridin-3-yl-oxy)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(2-oxo-1,2-dihydro-pyridin-3-yl-oxy)-N-thiazolo[5,4-b]pyridin-2-yl-benzamide,5-isopropoxy-3-([1,3,4]thiadiazol-2-ylsulfanyl)-N-thiazolo[5,4-b]-pyridine-2-yl-benzamide,5-isopropoxy-3-(4-methyl-[1,2,4]triazol-3-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-thiazol-2-ylsulfanyl-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(4H-[1,2,4]triazol-3-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-([1,3,4]thiadiazol-2-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(5-methylsulfanyl-[1,3,4]thiadiazol-2-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-isopropoxy-3-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-(tetrahydrofuran-3-yl-oxy)-N-thiazol-2-yl-3-(4H-[1,2,4]triazol-3-ylsulfanyl)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(4-methyl-thiazol-2-yl)-3-([1,3,4]thiadiazol-2-ylsulfanyl)-benzamide,5-(3-hydroxy-1-methyl-propoxy)-N-(4-methyl-thiazol-2-yl)-3-([1,3,4]thiadiazol-2-ylsulfanyl)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-([1,3,4]thiadiazol-2-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenylsulfanyl)-N-thiazol-2-yl-benzamide,3-(3-fluoro-phenylthio)-5-(2-hydroxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(pyridin-4-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methyl-pyridin-3-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(3-methyl-[1,2,4]-thiadiazol-5-yl)-benzamide,N-[3-hydroxymethyl-1,2,4-thiadiazol-5-yl]-3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)benzamide,5-(3-hydroxy-1-methylethoxy)-3-(4-methanesulfonylphenoxy)-N-[5-methyl-1,2,4-thiadiazol-3-yl]benzamide,5-(hydroxy-1-methylethoxy)-3-(4-methanesulfonylphenoxy)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(1,2,5-thiadiazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(4-trifluoromethyl-thiazol-2-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(4,5,6,7-tetrahydrobenzothiazol-2-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(pyridazin-3-yl)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(3-isopropyl-[1,2,4]-triazol-5-yl)-3-(4-methanesulfonylphenoxy)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(3-methyl-[1,2,4]-oxadiazol-5-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-thiazol-2-yl]-3-(4-methanesulfonylphenoxy)benzamide,N-(4-cyano-thiazol-2-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(1-hydroxymethyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-(pyridin-2-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(5-methyl-isothiazol-3-yl)benzamide,5-(3-hydroxy-cyclopentyloxy)-3-(4-methanesulfonylphenoxy)-N-(thiazol-2-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(5-methoxy-thiazol-2-yl)benzamide,5-(1-hydroxymethyl-2-methyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-(thiazol-2-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(1H-[1,2,3]triazol4-yl)benzamide,N-(1-acetyl-1H-pyrazol-3-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(pyrazol-3-yl)benzamide,N-(5,6-dihydro-4H-cyclopentathiazol-2-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)benzamide,5-(1-hydroxymethyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(thieno[3,2-d]thiazol-2-yl)benzamide,3-(3-fluoro-4-methanesulfonylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(4-methanesulfonylphenoxy)-5-(2-methoxy-1-methyl-ethoxy)-N-(pyrazol-3-yl)benzamide,3-(4-cyano-phenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(4-ethylsulfonylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(3-hydroxy-1-methyl-propoxy)-3-(4-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(4-ethanesulfonylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-isopropylsulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(4-hydroxy4-methyl4,5,6,6a-tetrahydro-3aH-cyclopentathiazol-2-yl)-3-(4-methanesulfonylphenoxy)benzamide,3-(4-dimethylcarbamoyl-phenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(4-acetylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-3-(1,3,4-thiadiazol-2-ylsulfanyl)benzamide,N-(1-ethyl-1H-pyrazol-3-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenoxy)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methoxycarbonylaminomethyl-phenoxy)-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide,5-(1-hydroxymethyl-propoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-methanesulfonylpyridin-3-yloxy)-5-(1-methoxymethyl-propoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-isopropoxy-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonylphenylsulfanyl)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-cyclopropyloxy-3-(4-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-methanesulfonylpyridin-3-yloxy)-5-(1-methoxymethyl-propoxy)-N-(pyrazol-3-yl)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(4-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(1-hydroxymethyl-propoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(6-ethanesulfonylpyridin-3-yloxy)-3-(2-methoxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,2-[3-(4-methanesulfonylphenoxy)-5-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-phenoxy]propionicacid tert-butyl ester,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-methoxy-1-methyl-ethoxy)-N-(pyrazol-3-yl)-benzamide,3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)-5-(tetrahydrofuran-3-yl)benzamide,N-(1-ethyl-1H-pyrazol-3-yl)-5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(pyrazol-3-yl)benzamide,3-(6-methanesulfonylpyridin-3-yloxy)-5-(2-methoxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-fluoro-1-fluoromethyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,2-[3-(4-methanesulfonylphenoxy)-5-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-phenoxy]propionicacid,3-(6-ethanesulfonylpyridin-3-yloxy)-5-isopropoxy-N-(pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-isopropoxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(pyrazol-3-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(pyridin-2-yl)benzamide,3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-thiazol-2-yl-benzamide-5-(2-fluoro-1-methyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-chloro-1-methyl-ethoxy)-3-(6-ethanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-N-(isoxazol-3-yl)-3-(6-methanesulfonylpyridin-3-yloxy)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(pyridin-2-yl)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(3-methyl-[1,2,4]-thiadiazol-5-yl)benzamide,3-(4-dimethylsulfamoylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(3-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(6-isopropylsulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(3-chloro-4-methanesulfonylphenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-3-(pyridin-3-yloxy)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-3-(pyridin-3-yloxy)benzamide,5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-3-(pyridin-4-yloxy)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)-3-(pyridin-4-yloxy)benzamide,2-[3-(6-ethanesulfonylpyridin-3-yloxy)-5-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-phenoxy]propionicacid and5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(3-fluoro-4-methanesulfonylphenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,and the pharmaceutically acceptable salts thereof.
 43. A compound inaccordance with claim 1 selected from the group consisting of:5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-N-thiazol-2-yl-benzamide,N-(4-hydroxymethyl-thiazol-2-yl)-3-(4-methanesulfonyl-phenoxy)-5-(1-methoxymethyl-propoxy)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-N-pyridin-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-N-(2-methylthiazol-4-yl)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-([1,3,4]thiadiazol-2-ylsulfanyl)-N-thiazol-2-yl-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-N-(3-methyl-[1,2,4]-thiadiazol-5-yl)-benzamide,5-(2-hydroxy-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(3-fluoro-4-methanesulfonyl-phenoxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-ethanesulfonyl-pyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-ethanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonyl-pyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-(6-ethanesulfonyl-pyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(isoxazol-3-yl)benzamide,5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonyl-pyridin-3-yloxy)-N-(pyrazol-3-yl)benzamideand the pharmaceutically acceptable salts thereof.
 44. A pharmaceuticalcomposition comprised of a compound in accordance with claim 1 incombination with a pharmaceutically acceptable carrier.
 45. Apharmaceutical composition in accordance with claim 44 furthercomprising a compound selected from the group consisting of: (a) otherglucokinase activators (b) bisguanides (c) PPAR agonists (d) insulin (e)somatostatin (f) α-glucosidase inhibitors, and (g) insulinsecretagogues.
 46. A method of treating diabetes in a mammalian patientin need of such treatment comprising administering to the patient acompound in accordance with claim 1 in an amount that is effective totreat diabetes.
 47. A method of treating obesity in a mammalian patientin need of such treatment comprising administering to the patient acompound in accordance with claim 1 in an amount that is effective totreat diabetes.